3 (5) -heteroaryl substituted pyrazoles as p38 kinase inhibitors

ABSTRACT

A class of pyrazole derivatives is described for use in treating p38 kinase mediated disorders. Compounds of particular interest are defined by Formula I  
                 
 
     wherein R 1 , R 2 , Ar 1  and HetAr 2  are as described in the specification.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. ProvisionalApplication Ser. No. 60/047,535 filed May 22, 1997.

FIELD OF THE INVENTION

[0002] This invention relates to a novel group of pyrazole compounds,compositions and methods for treating p38 kinase mediated disorders.

BACKGROUND OF THE INVENTION

[0003] Mitogen-activated protein kinases (MAP) is a family ofporline-directed serine/threonine kinases what activate their substratesby dual phosphorylation. The kinases are activated by a variety ofsignals including nutritional and osmotic stress, UV light, growthfactors, endotoxin and inflammatory cytokines. The p38 SNAP kinase groupis a MAP family of various isoforms, including p38α, p38β and p38γ, andis responsible for phosphorylating and activating transcription factors(e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g. MAPKAP-2 andMAPKAP-3). The p38 isoforms are activated by bacteriallipopolysaccharide, physical and chemical stress and by pro-inflammatorycytokines, including tumor necrosis factor (TNF-α) and interleukin-1(IL-1). The products of the p38 phosphorylation mediate the productionof inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.

[0004] TNF-α is a cytokine produced primarily by activated monocytes andmacrophages. Excessive or unregulated TNF production has been implicatedin mediating a number of diseases. Recent studies indicate that TNF hasa causative role in the pathogenesis of rheumatoid arthritis. Additionalstudies demonstrate that inhibition of TNF has broad application in thetreatment of inflammation, inflammatory bowel disease, multiplesclerosis and asthma.

[0005] TNF has also been implicated in viral infections, such as HIV,influenza virus, and herpes virus including herpes simplex virus type-1(HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV),varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6(HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8),pseudorabies and rhinotracheitis, among others.

[0006] IL-8 is another pro-inflammatory cytokine, which is produced bymononuclear cells, fibroblasts, endothelial cells, and keratinocytes,and is associated with conditions including inflammation.

[0007] IL-1 is produced by activated monocytes and macrophages and isinvolved in the inflammatory response. IL-1 plays a role in manypathophysiological responses including rheumatoid arthritis, fever andreduction of bone resorption.

[0008] TNF, IL-1 and IL-8 affect a wide variety of cells and tissues andare important inflammatory mediators of a wide variety of disease statesand conditions. The inhibition of these cytokines by inhibition of thep38 kinase is of benefit in controlling, reducing and alleviating manyof these disease states.

[0009] Various pyrazoles have previously been described. U.S. Pat. No.4,000,281, to Beiler and Binon, describes 4,5-aryl, heteroarylsubstituted pyrazoles with antiviral activity against both RNA and DNAviruses such as myxoviruses, adenoviruses, rhinoviruses, and variousviruses of the herpes group. WO 92/19615, published Nov. 12, 1992,describes pyrazoles as novel fungicides. U.S. Pat. No. 3,984,431, toCueremy and Renault, describes derivatives of pyrazole-5-acetic acid 5as having antiinflammatory activity. Specifically,[1-isobutyl-3,4-diphenyl-1H-pyrazol-5-yl]acetic acid is described. U.S.Pat. No. 3,245,093 to Hinsgen et al, describes a process for preparingpyrazoles. WO 83/00330, published Feb. 3, 1983, describes new processfor the preparation of diphenyl-3,4-methyl-5-pyrazole derivatives. WO95/06036, published for preparing pyrazole and its derivatives. U.S.Pat. No. 5,589,439, to T. Goto, et al., describes tetrazole derivativesand their use as herbicides. EP 515041 is describes pyrimidylsubstituted pyrazole derivatives as novel agricultural fungicides.Japanese Patent 4,145,081 describes pyrazolecarbxylic acid derivativesas herbicides used in paddy fields, dry fields as well asnon-agricultural areas. Japanese Patent 5,345,772 describes novelpyrazole derivatives having potent inhibitory activity againstacetylcholinesterase.

[0010] Pyrazoles have been described for use in the treatment ofinflammation. Japanese Patent 5,017,470 describes synthesis of pyrazolederivatives as anti-inflammatory, anti-rheumatic, anti-bacterial andanti-viral drugs. EP 115640, published Dec. 30, 1983, describes4-imidazolyl-pyrazole derivatives as inhibitors of thromboxanesynthesis.3-(4-Isopropyl-1-methylcyclohex-1-yl)-4-(imidazol-1-yl)-1H-pyrazole isspecifically described. WO 97/01551, published Jan. 16, 1997, describespyrazole compounds as adenosine antagonists.4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3-phenylpyrazole is specificallydescribed. U.S. Pat. No. 5,134,142, to Matsuo et al. describes1,5-diaryl pyrazoles as having anti-inflammatory activity.

[0011] U.S. Pat. No. 5,559,137 to Adams et al, describes novel pyrazoles(1,3,4,-substituted) as inhibitors of cytokines used in the treatment ofcytokine diseases. Specifically,3-(4-fluorophenyl)-1-(4-methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazoleis described. WO 96/03385, published Feb. 8, 1996, describes3,4-substituted pyrazoles, as having anti-inflammatory activity.Specifically,4-[1-ethyl-4-(4-pyridyl)-5-trifluoromethyl-1H-pyrazol-3-yl]benzenesulfonamideis described.

[0012] The invention's pyrazolyl compounds are found to show usefulnessas p38 kinase inhibitors.

DESCRIPTION OF THE INVENTION

[0013] A class of substituted pyrazolyl compounds useful in treating p38mediated disorders is defined by Formula I:

[0014] wherein

[0015] R¹ is selected from hydrido, alkyl, cycloalkyl, alkenyl, alkynyl,heterocyclyl, cycloalkylalkylene, halcalkyl, hydroxyalkyl, aralkyl,alkoxyalkyl, mercaptoalkyl, alkylthioalkylene, amino, alkylamino,arylamino, aminoalkyl, alkylaminoalkylene, heterocyclylalkylene,aminocarbonylalkylene, and alkylaminocarbonylalkylene; and

[0016] R² is selected from hydrido, alkyl, alkenyl, alkynyl,heterocyclyl, haloalkyl, heterocyclylalkyl, amino, alkylamino,aminoalkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl, carboxyalkyl,aminocarbonylamino, alkylaminocarbonylamino, alkylsulfonyl,aminosulfonyl, alkylsulfonylamino, aminosulfonylamino,alkylaminosulfonylamino, and alkynylamino; wherein the heterocyclyl andheterocyclylalkyl groups are optionally substituted with one or moreradicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,haloalkyl, amino, cyano, and hydroxy; and

[0017] Ar¹ is aryl optionally substituted with one or more radicalsindependently selected from halo, alkyl, alkenyl, alkynyl, alkoxy,alkenoxy, alkyldioxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino,aminocarbonyl, cyano, alkoxycarbonyl, formyl, aminosulfonyl, alkylamino,nitro, arylamino, alkylcarbonylamino, halosulfonyl, aminoalkyl, andhaloalkyl; and

[0018] HetAr² is pyridinyl, pyrimidinyl or quinolinyl optionallysubstituted with one or more radicals independently selected fromalkylthio, alkylsulfonyl, alkylsulfinyl, halo, alkyl, heterocyclyl,alkoxy, aralkoxy, haloalkyl, amino, cyano, aralkyl, alkylamino,cycloalkylamino, cycloalkenylamino, arylamino, alkynylamino, andaralkylamino; or

[0019] a pharmaceutically-acceptable salt or a tautomer thereof.

[0020] Compounds of Formula I would be useful for, but not limited to,the treatment of any disorder or disease state in a human, or othermammal, which is excacerbated or caused by excessive or unregulated TNFor p38 kinase production by such mammal. Accordingly, the presentinvention provides a method of treating a cytokine-mediated diseasewhich comprises administering an effective cytokine-interfering amountof a compound of Formula I, or a pharmaceutically acceptable salt ortautomer thereof.

[0021] Compounds of Formula I would be useful for, but not limited to,the treatment of inflammation in a subject, and for use as antipyreticsfor the treatment of fever. Compounds of the invention would be usefulto treat arthritis, including but not limited to, rheumatoid arthritis,spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis, osteoarthritis, gouty arthritisand other arthritic conditions. Such compounds would be useful for thetreatment of pulmonary disorders or lung is inflammation, includingadult respiratory distress syndrome, pulmonary sarcoidosis, asthma,silicosis, and chronic Pulmonary inflammatory disease. The compounds arealso useful for the treatment of viral and bacterial infections,including sepsis, septic shock, gram negative sepsis, malaria,meningitis, cachexia secondary to infection or malignancy, cachexiasecondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDSrelated complex), pneumonia, and herpesvirus. The compounds are alsouseful for the treatment of bone resorption diseases, such asosteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury,autoimmune disease including graft vs. host reaction and allograftrejections, cardiovascular diseases including atherosclerosis,thrombosis, congestive heart failure, and cardiac reperfusion injury,renal reperfusion injury, liver disease and nephritis, and myalgias dueto infection.

[0022] The compounds are also useful for the treatment of influenza,multiple sclerosis, cancer, diabetes, systemic lupus erthrematosis(SLE), skin-related conditions such as psoriasis, eczema, burns,dermatitis, keloid formation, and scar tissue formation. Compounds ofthe invention also would be useful to treat gastrointestinal conditionssuch as inflammatory bowel disease, Crohn's disease, gastritis,irritable bowel syndrome and ulcerative colitis. The compounds wouldalso be useful in the treatment of ophthalmic diseases, such asretinitis, retinopathies, uveitis, ocular photophobia, and of acuteinjury to the eye tissue. Compounds of the invention also would beuseful for treatment of angiogenesis, including neoplasia; metastasis;ophthalmological conditions such as corneal graft rejection, ocularneovascularization, retinal neovascularization includingneovascularization following injury or infection, diabetic retinopathy,retrolental fibroplasia and neovascular glaucoma; ulcerative diseasessuch as gastric ulcer; pathological, but non-malignant, conditions suchas hemaginomas, including invantile hemaginomas, angiofibroma of thenasopharynx and avascular necrosis of bone; diabetic nephropathy andcardiomyopathy; and disorders of the female reproductive system such asendometriosis. The compounds of the invention may also be useful forpreventing the production of cyclooxygenase-2.

[0023] Besides being useful for human treatment, these compounds arealso useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. Morepreferred animals include horses, dogs, and cats.

[0024] The present compounds may also be used in co-therapies, partiallyor completely, in place of other conventional antiinflammatories, suchas together with steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDS,immunosuppressive agents, 5-lipoxygenase inhibitors, LTB₄ antagonistsand LTA₄ hydrolase inhibitors.

[0025] As used herein, the term “TNF mediated disorder” refers to anyand all disorders and disease states in which TNF plays a role, eitherby control of TNF itself, or by TNF causing another monokine to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to TNF, wouldtherefore be considered a disorder mediated by TNF.

[0026] As used herein, the term “p38 mediated disorder” refers to anyand all disorders and disease states in which p38 plays a role, eitherby control of p38 itself, or by p38 causing another factor to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to p38, wouldtherefore be considered a disorder mediated by p38.

[0027] As TNF-β has close structural homology with TNF-α (also known ascachectin), and since each induces similar biologic responses and bindsto the same cellular receptor, the synthesis of both TNF-α and TNF-β areinhibited by the compounds of the present invention and thus are hereinreferred to collectively as “TNF” unless specifically delineatedotherwise.

[0028] A preferred class of compounds consists of those compounds ofFormula I wherein

[0029] R¹ is selected from hydrido, lower alkyl, lower cycloalkyl, lowercycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower alkenyl,lower alkynyl, lower heterocyclyl, lower aralkyl, lower alkoxyalkyl,lower mercaptoalkyl, lower alkylthioalkylene, amino, lower alkylamino,lower arylamino, lower aminoalkyl, lower alkylaminoalkylene, lowerheterocyclylalkylene, lower aminocarbonylalkylene, and loweralkylaminocarbonylalkylene; and

[0030] R² is selected from hydrido, lower alkyl, lower alkenyl, loweralkynyl, lower haloalkyl, lower heterocyclyl, lowerheterocyclylalkylene, amino, lower alkylamino, lower alkynylamino, loweraminoalkyl, lower alkylthio, lower carboxy, lower alkoxycarbonyl, lowercarboxyalkyl, lower aminocarbonylamino, lower alkylaminocarbonylamino,lower alkylsulfonyl, lower aminosulfonyl, lower alkylsulfonylamino,lower aminosulfonylamino, and lower alkylaminosulfonylamino, wherein theheterocyclyl and heterocyclylalkyl groups are optionally substitutedwith one or more radicals independently selected from lower alkylthio,lower alkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, loweralkoxy, aryloxy, lower heterocyclyl, lower haloalkyl, amino, and cyano;and

[0031] Ar¹ is selected from phenyl, biphenyl, and naphthyl, wherein Ar¹is optionally substituted with one or more radicals independentlyselected from lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halo,lower alkyl, lower alkenyl, lower alkynyl, lower alkylsulfinyl, cyano,lower alkoxycarbonyl, aminocarbonyl, formyl, lower alkylcarbonylamino,lower haloalkyl, lower alkoxy, lower alkenyloxy, lower alkyldioxy,amino, lower alkylamino, lower aminoalkyl, arylamino, nitro, andhalosulfonyl; and

[0032] HetAr² is pyridinyl or pyrimidinyl optionally substituted withone or more radicals independently selected from lower alkylthio, loweralkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, lowerheterocyclyl, lower alkoxy, lower aralkoxy, lower haloalkyl, amino,cyano, lower aralkyl, lower alkylamino, lower cycloalkylamino, lowerarylamino, lower alkynylamino, and lower aralkylamino; or

[0033] a pharmaceutically-acceptable salt or tautomer thereof.

[0034] A class of compounds of particularly interest consists of thesecompounds of Formula I wherein

[0035] R¹ is selected from hydrido, methyl, ethyl, isopropyl,tert-butyl, isobutyl, trichloroethyl, pentafluoroethyl,heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, vinyl, allyl, ethynyl, propargyl, morpholinyl,piperidinyl, piperazinyl, benzyl, phenylethyl, morpholinomethyl,morpholinoethyl, pyrrolidinylmethyl, piperazinylmethyl,piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl,ethoxymethyl, amino, methylamino, dimethylamino, phenylamino,methylaminomethyl, dimethylaminomethyl, methylaminoethyl,dimethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl,cyclohexylmerhyl, hydroxymethyl, hydroxyethyl, methylthio, andmethylthiomethyl; and

[0036] R² is selected from hydrido, methyl, ethyl, propyl, isopropyl,tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, amino,N-methylamino, N,N-dimethylamino, ethynylamino, propargylamino,piperidinyl, piperazinyl, morpholinomethyl, pyrrolidinylmethyl,piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl,thiazolylmethyl, oxazolylmethyl, pyrimidinylmethyl, quinolylmethyl,isoquinolinylmethyl, imidazolylmethyl, benzimidazolylmethyl,furylmethyl, pyrazinylmethyl, aminocarbonylamino,methylaminocarbonylamino, dimethylaminocarbonylamino,ethylaminocarbonylamino, diethylaminocarbonylamino, methylsulfonylamino,ethylsulfonylamino, aminosulfonylamino, methylaminosulfonylamino,dimethylaminosulfonylamino, ethylaminosulfonylamino, anddiethylaminosulfonylamino; and

[0037] Ar¹ is selected from phenyl, biphenyl, and naphthyl, wherein Ar¹is optionally substituted with one or more radicals independentlyselected from methylthio, methylsulfinyl, methylsulfonyl, fluoro,chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl,isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl,trichloromethyl, dichloromethyl, chloromethyl, allyl, vinyl, ethynyl,propargyl, methoxy, ethoxy, propyloxy, n-butoxy, amino, methylamino,ethylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl,N-methyl, N-phenylamino, phenylamino, diphenylamino, nitro, andchlorosulfonyl; and

[0038] HetAr² is selected from pyridinyl and pyrimidinyl, wherein HetAr²is optionally substituted with one or more radicals independentlyselected from methylthio, methylsulfinyl, methylsulfonyl, fluoro,chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, methoxyl,ethoxyl, phenoxyl, benzoxyl, phenethyl, trifluoromethyl, fluoromethyl,difluoromethyl, amino, benzylamino, propargylamino, cyclopropylamino,cyclobutylamino, cyclopentylamino, and cyano; or

[0039] a pharmaceutically-acceptable salt or tautomer thereof.

[0040] A class of compounds of specific interest consists of thosecompounds of Formula I wherein

[0041] R¹ is hydrido, methyl, ethyl, hydroxyethyl, propargyl,dimethylaminoethyl or morpholinoethyl; and

[0042] R² is selected from hydrido, methyl, ethyl, amino,aminocarbonylamino, methylaminocarbonylamino, methylsulfonylamino,aminosulfonylamino, and methylaminosulfonylamino; and

[0043] Ar¹ is phenyl optionally substituted with one or more radicalsindependently selected from methylthio, methylsulfinyl, methylsulfonyl,fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl,tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl,aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl,fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, methoxy,ethoxy, propyloxy, n-butoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, aminomethyl, aminoethyl, N-methyl,N-phenylamino, phenylamino, diphenylamino, nitro, and chlorosulfonyl;and

[0044] HetAr² is optionally substituted with one or more radicalsindependently selected from methylthio, methylsulfinyl, methylsulfonyl,fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl,methoxyl, ethoxyl, phenoxyl, benzoxyl, trifluoromethyl, fluoromethyl,difluoromethyl, amino, propargylamino, and cyano; or

[0045] a pharmaceutically-acceptable salt or a tautomer thereof.

[0046] A class of compounds of very specific interest consists of thosecompounds of Formula I wherein

[0047] R¹ is hydrido or methyl; and

[0048] R² is hydrido or methyl; and

[0049] Ar¹ is phenyl which is optionally substituted with one or moreradicals independently selected fluoro, chloro, methyl, ethyl,trifluoromethyl, methoxy, ethoxy, dimethylamino, and nitro; and

[0050] HetAr² is optionally substituted with one or more radicalsindependently selected from methyl, chloro, fluoro, and trifluoromethyl;or

[0051] a pharmaceutically-acceptable salt or tautomer thereof.

[0052] A family of specific compounds of particular interest withinFormula I consists of compounds, and tautomers andpharmaceutically-acceptable salts thereof, as follows:

[0053] 4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine;

[0054] 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine;

[0055]N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide;

[0056]N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylsulfamide;

[0057] [4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]urea;

[0058] [4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]sulfamide;

[0059] 4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazol-5-amine;

[0060]N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylurea;

[0061] 4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine;

[0062] 4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine;

[0063] 4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol;

[0064]4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine;

[0065]4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine;

[0066] 4-[4-(4-chlorophenyl)-1H-pyrazol-3-yl]pyridine;

[0067] 4-(4-phenyl-1H-pyrazol-5-yl)pyridine;

[0068]1-methyl-4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]]piperidine;and

[0069]1-methyl-4-[2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-1-yl]piperidine.

[0070] The term “hydride” denotes a single hydrogen atom (H). Thishydrido radical may be attached, for example, to an oxygen atom to forma hydroxyl radical or two hydrido radicals may be attached to a carbonatom to form a methylene (—CH₂—) radical. Where used, either alone orwithin other terms such as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl”,“hydroxyalkyl”, “mercaptoalkyl”, the term “alkyl” embraces linear orbranched radicals having one to about twenty carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkylradicals are “lower alkyl” radicals having one to about ten carbonatoms. Most preferred are lower alkyl radicals having one to about sixcarbon atoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl and the like. The term “alkenyl” embraces linear or branchedradicals having at least one carbon-carbon double bond of two to abouttwenty carbon atoms or, preferably, two to about twelve carbon atoms.More preferred alkenyl radicals are “lower alkenyl” radicals having twoto about six carbon atoms. Examples of alkenyl radicals include ethenyl,propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms“alkenyl” and “lower alkenyl”, embrace radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations. The term“alkynyl” embraces linear or branched radicals having at least onecarbon-carbon triple bond of two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkynylradicals are “lower alkynyl” radicals having two to about six carbonatoms. Examples of alkynyl radicals include propargyl, 1-propynyl,2-propynyl, 1-butyne, 2-butenyl and 1-pentynyl. The term “cycloalkyl”embraces saturated carbocyclic radicals having three to about twelvecarbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl”radicals having three to about eight carbon atoms. Examples of suchradicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.The term “cycloalkylalkylene” embraces alkyl radicals substituted with acycloalkyl radical. More preferred cycloalkylalkylene radicals are“lower cycloalkylalkylene” which embrace lower alkyl radicalssubstituted with a lower cycloalkyl radical as defined above. Examplesof such radicals include cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl and cyclohexylmethyl. The term “cycloalkenyl” embracespartially unsaturated carbocyclic radicals having three to twelve carbonatoms and one or two double bonds but not necessarily conjugated(“cycloalkyldienyl”). More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.The term “cycloalkenylalkylene” embraces alkyl radicals substituted witha cycloalkenyl radical. More preferred cycloalkenylalkylene radicals are“lower cycloalkenylalkylene” which embrace lower alkyl radicalssubstituted with a lower cycloalkenyl radical, as defined above.Examples of such radicals include cyclobutenylmethyl,cyclopentenylmethyl and cyclohexenylmethyl. The term “halo” meanshalogens such as fluorine, chlorine, bromine or iodine. The term“haloalkyl” embraces radicals wherein any one or more of the alkylcarbon atoms is substituted with halo as defined above. Specificallyembraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals, Amonohaloalkyl radical, for one example, may have either an iodo, bromo,chloro or fluoro atom within the radical. Dihalo and polyhaloalkylradicals may have two or more of the same halo atoms or a combination ofdifferent halo radicals. “Lower haloalkyl” embraces radicals having oneto six carbon atoms. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichioroethyl and dichloropropyl. The term“hydroxyalkyl” embraces linear or branched alkyl radicals having one toabout ten carbon atoms, any one of which may be substituted with one ormore hydroxyl radicals. More preferred hydroxyalkyl radicals are “lowerhydroxyalkyl” radicals having one to six carbon atoms and one or morehydroxyl radicals. Examples of such radicals include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms“alkoxy” and “alkyloxy” embrace linear or branched oxy-containingradicals each having alkyl portions of one to about ten carbon atoms.More preferred alkoxy radicals are “lower alkoxy” radicals having one tosix carbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. The term “alkoxyalkyl” embraces alkylradicals having one or more alkoxy radicals attached to the alkylradical to form, for example, monoalkoxyalkyl and dialkoxyalkylradicals. The “alkoxy” radicals may be further Substituted with one ormore halo atoms, such as fluoro, chloro or bromo, to provide“haloalkoxy” radicals.

[0071] The term “aryl”, alone or in combination, means a carbocyclicaromatic system containing one, two or three rings wherein such ringsmay be attached together in a pendent manner or may be fused. Morepreferred aryl are 6-12 membered aryl radicals. Examples of suchradicals include phenyl, naphthyl, tetrahydronaphthyl, indane andbiphenyl. Aryl moieties may also be substituted at a substitutableposition with one or more substituents selected independently from, forexample, halo, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy,alkylthio, alkylsulfinyl, alkylsulfonyl, amino, aminocarbonyl, cyano,alkoxycarbonyl, formyl, aminosulfonyl, alkylamino, nitro, arylamino,alkylcarbonylamino, halosulfonyl, aminoalkyl, and haloalkyl,alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, aralkoxy, hydroxyl,acyl, carboxy, aminocarbonyl, andaralkoxycarbonyl. The term “alkyldioxy” encompasses an alkyldioxybridge, such as a methylenedioxy bridge, between two carbon ring atomsof an aryl moiety.

[0072] The term “heterocyclyl” embraces saturated, partially unsaturatedand unsaturated heteroatom-containing ring-shaped radicals, which canalso be called “heterocyclyl”, “heterocycloalkenyl” and “heteroaryl”correspondingly, where the heteroatoms may be selected from nitrogen,sulfur and oxygen. Examples of saturated heterocyclyl radicals includesaturated 3 to 6-membered heteromonocyclic group containing 1 to 4nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g.morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,thiazolidinyl, etc.). Examples of partially unsaturated heterocyclylradicals include dihydrothiophene, dihydropyran, dihydrofuran anddihydrothiazole. Heterocyclyl radicals may include a pentavalentnitrogen, such as in tetrazolium and pyridinium radicals. The term“heteroaryl” embraces unsaturated heterocyclyl radicals. Examples ofheteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclicgroup containing 1 to 4 nitrogen atoms, for example, pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl,etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to 5nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.;unsaturated 3 to 6-membered heteromonocyclic group containing an oxygenatom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing a sulfur atom, for example, thienyl,etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g.benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.;unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl,etc.) and the like. The term “heteroaryl” also embraces radicals whereheterocyclyl radicals are fused with aryl radicals. Examples of suchfused bicyclic radicals include benzofuran, benzothiophene, and thelike. Said heterocyclyl group may have 1 to 3 substituents such asalkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino. The term“heterocyclylalkylene” embraces heterocyclyl-substituted alkyl radicals.More preferred heterocyclylalkylene radicals are “lowerheterocyclylalkylene” radicals having one to six carbon atoms and aheterocyclyl radical.

[0073] The term “alkylthio” embraces radicals containing a linear orbranched alkyl radical, of one to about ten carbon atoms attached to adivalent sulfur atom. More preferred alkylthio radicals are “loweralkylthio” radicals having alkyl radicals of one to six carbon atoms.Examples of such lower alkylthio radicals are methylthio, ethylthio,propylthio, butylthio and hexylthio. The term “alkylthioalkylene”embraces radicals containing an alkylthio radical attached through thedivalent sulfur atom to an alkyl radical of one to about ten carbonatoms. More preferred alkylthioalkylene radicals are “loweralkylthioalkylene” radicals having alkyl radicals of one to six carbonatoms. Examples of such lower alkylthioalkylene radicals includemethylthiomethyl. The term “alkylsulfinyl” embraces radicals containinga linear or branched alkyl radical, of one to about ten carbon atoms,attached to a divalent —S(═O)— radical. More preferred alkylsulfinylradicals are “lower alkylsulfinyl”, radicals having alkyl radicals ofone to six carbon atoms. Examples of such lower alkylsulfinyl radicalsinclude methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.The term “sulfonyl”, whether used alone or linked to other terms such as“alkylsulfonyl”, or “halosulfonyl” denotes a divalent radical, —SO₂—.“Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical,where alkyl is defined as above. More preferred alkylsulfonyl radicalsare “lower alkylsulfonyl” radicals having one to six carbon atoms.Examples of such lower alkylsulfonyl radicals include methylsulfonyl,ethylsulfonyl and propylsulfonyl. The “alkylsulfonyl” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide haloalkylsulfonyl radicals. The term “halosulfonyl”embraces halo radicals attached to a sulfonyl radical. Examples of suchhalosulfonyl radicals include chlorosulfonyl and bromosulfonyl. Theterms “sulfamyl”, “aminosulfonyl” and “sulfonamidyl” denote NH₂O₂S—.

[0074] The term “carbonyl”, whether used alone or with other terms, suchas “alkoxycarbonyl”, denotes —(C═O)—. The terms “carboxy” or “carboxyl”,whether used alone or with other terms, such as “carboxyalkyl”, denotes—CO₂H. The term “carboxyalkyl” embraces alkyl radicals substituted witha carboxy radical. More preferred are “lower carboxyalkyl”.radicalswhich embrace carboxy-substituted lower alkyl radicals, as definedabove. Examples of such lower carboxyalkyl radicals includecarboxymethyl, carboxyethyl and carboxypropyl. The term “alkoxycarbonyl”means a radical containing an alkoxy radical, as defined above, attachedvia an oxygen atom to a carbonyl radical. More preferred are “loweralkoxycarbonyl” radicals with alkyl portions having one to six carbons.Examples of such lower alkoxycarbonyl (ester) radicals includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl andhexyloxycarbonyl. The term “alkoxycarbonylalkylene” embraces alkylradicals substituted with an alkoxycarbonyl radical as defined above.More preferred are “lower alkoxycarbonylalkylene” radicals with alkylportions having one to six carbons. Examples of such loweralkoxycarbonylalkylene radicals include methoxycarbonylmethylene,ethoxycarbonylmethylene, methoxycarbonylethylene andethoxycarbonylethylene. The term “alkylcarbonyl”, includes radicalshaving alkyl radicals attached to a carbonyl radical. Examples of suchradicals include methylcarbonyl, ethylcarbonyl, propylcarbonyl,butylcarbonyl, and pentylcarbonyl. The term “aralkyl” embracesaryl-substituted alkyl radicals. Preferred aralkyl radicals are “loweraralkyl”, having lower alkyl groups substituted with one or more arylgroups. Examples of such groups include benzyl, diphenylmethyl,triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in saidaralkyl may be additionally substituted with halo, alkyl, alkoxy,haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl areinterchangeable. The term “heterocyclylalkylene” embraces saturated,partially unsaturated and unsaturated heterocyclyl-substituted alkylradicals such as pyrrolidinylmethyl, pyridylmethyl, quinolylmethyl,thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl inheteroaralkyl (unsaturated heterocyclyl-substituted alkyl radicals) maybe additionally substituted with halo, alkyl, alkoxy, haloalkyl andhaloalkoxy. The term “aryloxy” embraces aryl radicals attached throughan oxygen atom to other radicals. The term “aralkoxy” embraces aralkylradicals attached through an oxygen atom to other radicals.

[0075] The term “aminoalky”, embraces alkyl radicals substituted withamino radicals. More preferred are “lower aminoalkyl” radicals. Examplesof such radicals include aminomethyl, aminoethyl, and the like. The term“alkylamino” denotes amino groups which are substituted with one or twoalkyl radicals. Preferred are “lower alkylamino” radicals having alkylportions having one to six carbon atoms. Suitable lower alkylamino maybe monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such asN-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or thelike. The term “arylamino” denotes amino groups which are substitutedwith one or two aryl radicals, such as N-phenylamino. The “arylamino”radicals may be further substituted on the aryl ring portion of theradical. The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH. The term “alkylaminocarbonyl” denotes an aminocarbonyl groupwhich has been substituted with one or two alkyl radicals on the aminonitrogen atom. Preferred are “N-alkylaminocarbonyl” and“N,N-dialkylaminocarbonyl” radicals. More preferred are “lowerN-alkylaminocarbonyl” and “lower N,N-dialkylaminocarbonyl” radicals withlower alkyl portions as defined above. The term “aminocarbonylamino”embraces radicals having one or more aminocarbonyl radicals attached toan amino radical. The term “alkylaminocarbonylamino” embraces radicalshaving one or more alkyl radicals attached to an aminocarbonylaminoradical. Preferred are “lower alkylaminocarbonylamino” radicals withlower alkyl portions as defined above. The term “alkylcarbonylamino”embraces amino groups which are substituted with one or morealkylcarbonyl radicals. More preferred alkylcarbonylamino radicals are“lower alkylcarbonylamino” having lower alkylcarbonyl radicals asdefined above attached to amino radicals. The term “alkylaminoalkylene”embraces radicals having one or more alkyl radicals attached to anaminoalkyl radical. The term “alkylsulfonylamino” embraces radicalshaving one or more alkylsulfonyl radicals attached to an amino radical.Preferred are “lower alkylsulfonylamino” radicals with lower alkylportions as defined above. The term “aminosulfonylamino” embracesradicals having one or more aminosulfonyl radicals attached to an aminoradical. The term “alkylaminosulfonylamino” embraces radicals having oneor more alkyl radicals attached to an aminosulfonylamino radical.Preferred are “lower alkylaminosulfonylamino” radicals with lower alkylportions as defined above.

[0076] The additional terms used to describe the substituents of thepyrazole ring and not specifically defined herein are defined in asimilar manner to that illustrated in the above definitions. As above,more preferred substituents are those containing “lower” radicals.Unless otherwise defined to contrary, the term “lower” as used in thisapplication means that each alkyl radical of a pyrazole ring substituentcomprising one or more alkyl radicals has one to about six carbon atoms;each alkenyl radical of a pyrazole ring substituent comprising one ormore alkenyl radicals has two to about six carbon atoms; each alkynylradical of a pyrazole ring substituent comprising one or more alkynylradicals has two to about six carbon atoms; each cycloalkyl orcycloalkenyl radical of a pyrazole ring substituent comprising one ormore cycloalkyl and/or cycloalkenyl radicals is a 3 to 8 membered ringcycloalkyl or cycloalkenyl radical, respectively; each aryl radical of apyrazole ring substituent comprising one or more aryl radicals is amonocyclic aryl radical; and each heterocyclyl radical of a pyrazolering substituent comprising one or more heterocyclyl radicals is a 4-8membered ring heterocyclyl.

[0077] The present invention comprises the tautomeric forms of compoundsof formula I. As illustrated below, the pyrazoles of Formula I and I′are magnetically and structurally equivalent because of the prototropictautomeric nature of the hydrogen:

[0078] The present invention also comprises compounds of Formula Ihaving one or more asymmetric carbons. It is known to those skilled inthe art that those pyrazoles of the present invention having asymmetriccarbon atoms may exist in diastereomeric, racemic, or optically activeforms. All of these forms are contemplated within the scope of thisinvention. More specifically, the present invention includesenantiomers, diastereomers, racemic mixtures, and other mixturesthereof.

[0079] The present invention comprises a pharmaceutical composition forthe treatment of a TNF mediated disorder, a p38 kinase mediateddisorder, inflammation, and/or arthritis, comprising atherapeutically-effective amount of a compound of Formula I, or atherapeutically-acceptable salt or tautomer thereof, in association withat least one pharmaceutically-acceptable carrier, adjuvant or diluent.

[0080] The present invention also comprises a therapeutic method oftreating a TNF mediated disorder, a p38 kinase mediated disorder,inflammation and/or arthritis in a subject, the method comprisingtreating a subject having or susceptible to such disorder or conditionwith a therapeutically-effective amount of a compound of Formula I

[0081] wherein

[0082] R¹ is selected from hydrido, alkyl, cycloalkyl, alkenyl, alkynyl,heterocyclyl, cycloalkylalkylene, haloalkyl, hydroxyalkyl, aralkyl,alkoxyalkyl, mercaptoalkyl, alkylthioalkylene, amino, alkylamino,arylamino, aminoalkyl, alkylaminoalkylene, heterocyclylalkylene,aminocarbonylalkylene, and alkylaminocarbonylalkylene; and

[0083] R² is selected from hydrido, alkyl, alkenyl, alkynyl,heterocyclyl, haloalkyl, heterocyclylalkyl, amino, alkylamino,aminoalkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl, carboxyalkyl,aminocarbonylamino, alkylaminocarbonylamino, alkylsulfonyl,aminosulfonyl, alkylsulfonylamino, aminosulfonylamino,alkylaminosulfonylamino, and alkynylamino; wherein the heterocyclyl andheterocyclylalkyl groups are optionally substituted with one or moreradicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,haloalkyl, amino, cyano, and hydroxy; and

[0084] Ar¹ is aryl optionally substituted with one or more radicalsindependently selected from halo, alkyl, alkenyl, alkynyl, alkoxy,alkenoxy, alkyldioxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino,aminocarbonyl, cyano, alkoxycarbonyl, formyl, aminosulfonyl, alkylamino,nitro, arylamino, alkylcarbonylamino, halosulfonyl, aminoalkyl, andhaloalkyl; and

[0085] HetAr² is pyridinyl, pyrimidinyl or quinolinyl optionallysubstituted with one or more radicals independently selected fromalkylthio, alkylsulfonyl, alkylsulfinyl, halo, alkyl, heterocyclyl,alkoxy, aralkoxy, haloalkyl, amino, cyano, aralkyl, alkylamino,cycloalkylamino, cycloalkenylamino, arylamino, alkynylamino, andaralkylamino; or

[0086] a pharmaceutically-acceptable salt or a tautomer thereof.

[0087] Also included in the family of compounds of Formula I are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, A-hydroxybutyric, galactaric andgalacturonic acid. Suitable pharmaceutically-acceptable base additionsalts of compounds of Formula I include metallic salts and organicsalts. More preferred metallic salts include, but are not limited toappropriate alkali metal (group IIa) salts, alkaline earth metal (groupIIa) salts and other physiological acceptable metals. Such salts can bemade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc. Preferred organic salts can be made from tertiary amines andquaternary ammonium salts, including in part, tromethamine,diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine. All of these salts may be prepared by conventional means formthe corresponding compound of Formula I by reacting, for example, theappropriate acid or base with the compound of Formula I.

General Synthetic Procedures

[0088] The compounds of the invention can be synthesized according tothe following procedures of Schemes I-VI wherein the R¹-R³ substituentsand Ar¹, HetAr² are as defined for Formula I, above, except wherefurther noted.

[0089] Scheme I shows he three step preparation of the pyrazole 5 of thepresent invention. In step 1, the reaction of arylmethyl derived ketone1 with pyridine derived aldehyde 2 either in a solvent such as benzeneor toluene in the presence of a base such as pyridine or in a mixture ofacids such as acetic acid and hydrogen bromide gives the α,β-unsaturatedketone 3. In step 2, in the presence of base such as sodium hydroxide,α,β-unsaturated ketone 3 is converted to the corresponding epoxide 4 bythe treatment with hydrogen peroxide solution at room temperature. Instep 3, epoxide 4 is condensed with hydrazine in a suitable solvent suchas ethanol at temperature ranging up to the boiling point to formpyrazole 5. Alternatively, pyrazole 5 can be prepared by treatment of 3with tosyl hydrazide in the presence of an acid such as acetic acid atreflux.

[0090] Scheme II shows the synthesis of pyrazole 12 containing aheteroaromatic ring by three routes. In Route 1, ketone 6 is condensedwith hydrazine 7 to give substituted hydrazine 9, which is then reactedwith acyl halide or anhydride 10 at low temperature to provide acylhydrazone 11. Upon heating at temperature up to 200° C., hydrazone 11 isconverted to pyrazole 12. In Route 2, acyl hydrazone 11 is formeddirectly by reaction of ketone 6 with acyl hydrazide 8 at roomtemperature. Acyl hydrazide 8 may be formed by reaction of hydrazinewith a carboxylic acid ester. Heating 11 as above then provides pyrazole12. In Route 3, ketone 6 is treated with acyl hydrazide 8 at from roomtemperature to −20° C. to give pyrazole 12 directly. Alternatively, thiscondensation may be carried out in an acidic solvent, such as aceticacid, or in a solvent containing acetic acid.

[0091] Cyanoketone 13 may be synthesized according to the proceduredescribed by I. Lantos et al in J. Org. Chem., volume 53, pp. 4223-4227(1988) for the synthesis of the p-fluoro compound (X=p−F). Thisprocedure, which is incorporated herein by reference, can be used tosynthesize cyanoketones such as 13 wherein X is selected from, forexample, halogen, alkyl and alkoxy. Cyanoketones such as 13 may beconverted to pyrazoles 14 by reaction with a hydrazine in a suitablesolvent, such as benzene or toluene. A catalyst such as acetic acid maybe employed. When hydrazine itself is employed, the ring nitrogen atomsof the pyrazole thus obtained bear no substituent except hydrogen on oneof the ring nitrogen atoms. When a substituted hydrazine, such asmethylhydrazine is employed, the product pyrazole 14 bears a substituenton the ring nitrogen atom adjacent to the aminated ring carbon atom, asshown in Scheme 1. The resultant aminopyrazole 14 may be acylated orsulfonylated to form substituted aminopyrazole 15 by treatment with asuitably activated carboxylic or sulfonic acid in a suitable solventsuch as pyridine. Examples of a suitably activated carboxylic acidinclude acetic anhydride or benzoyl chloride. Examples of a suitablyactivated sulfonic acid include methanesulfonyl chloride,p-toluenesulfonyl chloride or sulfamyl chloride.

[0092] Scheme IV illustrates the synthesis of 3-pyridyl-4-aryl-pyrazolesof the present invention. Benzoate 16 is first reacted with pyridine 17in the presence of a base, such as an alkali metal alkoxide (preferablysodium methoxide), in a suitable solvent, such as tetrahydrofuran.Subsequent treatment with an acid, preferably a mineral acid such ashydrochloric acid, yields the desoxybenzoin 18. Desoxybenzoin 18 is thenconverted to ketone 19 by treatment with an excess of dimethylformamidedimethyl acetal. Ketone 19 is then reacted with hydrazine in a suitablesolvent such as ethanol to yield a mixture of pyrazoles 20 and 21. InScheme IV, R⁴ represents one or more radicals independently selectedfrom the optional substituents previously defined for Ar¹; and R⁵represents one or more radicals independently selected from the optionalsubstituents previously defined for HetAr².

[0093] The 3-pyrimidinyl-4-aryl-pyrazoles of the present invention canbe synthesized in the manner of Scheme IV by replacing pyridine 17 withthe corresponding pyrimidine.

[0094] In Scheme V, hydroxyalkyl pyrazoles 22 and 23 are converted tosulfonate derivatives by reaction with an alkyl- or arylsulfonyl halide.These sulfonates are then reacted with ammonia or primary amines orsecondary amines to give the corresponding 1-amino-pyrazoles 24 and 25,respectively. In Scheme V, n is 1, 2, 3, 4 or 5; R⁴ and R⁵ are asdefined in Scheme IV; R⁶ and R⁷ are independently selected, for example,from hydrogen, alkyl and aryl, or together with the nitrogen atom towhich they are attached form a 4-8 membered ring that may contain one ormore additional heteroatoms selected from oxygen, nitrogen or sulfur.

[0095] Scheme VI is similar to Scheme IV except that desoxybenzoin 18 isfirst reacted with hydrazine in a suitable solvent such as ethanol toyield hydrazine 26. Hydrazine 26 is then converted to pyrazole 20(rather than a mixture of pyrazoles 20 and 21 as in Scheme IV) bytreatment with an excess of dimethylformamide dimethyl acetal. In SchemeVI, R⁴ and R⁵ are as defined in Scheme V.

[0096] The following examples contain detailed descriptions of themethods of preparation of compounds of Formula I. These detaileddescriptions fall within the scope, and serve to exemplify, the abovedescribed General Synthetic Procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are in Degrees centigrade unlessotherwise indicated. All compounds showed NMR spectra consistent withtheir assigned structures. In some cases, the assigned structures wereconfirmed by nuclear Overhauser effect (NOE) experiments.

[0097] The following abbreviations are used:

[0098] HCl—hydrochloric acid

[0099] MgSO₄—magnesium sulfate

[0100] Na₂SO₄—sodium sulfate

[0101] NaIO₄—sodium periodate

[0102] NaHSO₃—sodium bisulfite

[0103] NaOH—sodium hydroxide

[0104] KOH—potassium hydroxide

[0105] P₂O₅—phosphorus pentoxide

[0106] MeOH—methanol

[0107] EtOH—ethanol

[0108] HOAc (or AcOH)—acetic acid

[0109] EtOAc—ethyl acetate

[0110] H₂O—water

[0111] H₂O₂—hydrogen peroxide

[0112] CH₂Cl₂—methylene chloride

[0113] NaOMe—sodium methoxide

[0114] h—hour

[0115] hr—hour

[0116] min—minutes

[0117] THF—tetrahydrofuran

[0118] TLC—thin layer chromatography

[0119] DSC—differential scanning calorimetry

[0120] b.p.—boiling point

[0121] m.p.—melting point

[0122] eq—equivalent

Step 1: Preparation of 3-phenyl-4-(4-pyridyl)-3-butene-2-one

[0123] 3-Phenyl-4-(4-pyridyl)-3-butene-2-one was prepared by the methodof Reichert and Lechner, Arzneim.-Forsch. 15, 36 (1965), which isincorporated by reference herein.

Step 2: Preparation of 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone

[0124] To a stirred solution of 3-phenyl-4-(4-pyridyl)-3-butene-2-one(step 1) (500 mg, 2.24 mmol) in methanol (10 ml) at room temperature wasadded an aqueous solution (9 ml) of sodium hydroxide (100 mg, 2.24 mmol)and hydrogen peroxide (0.5 ml of 30% aqueous solution, 4.4 mmol). Afterstirring for 2 hours, sodium chloride was added and the reaction wasextracted with ethyl acetate. The combined organic layers were driedover magnesium sulfate, filtered, and concentrated in vacuo to providethe crude 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone (385 mg, 65%) asan oil. This was used in the next step without further purification.

Step 3: Preparation of 4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine

[0125] A solution of 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone (step2) (350 mg, 1.46 mmol) and anhydrous hydrazine (0.7 ml, 20 mmol) inethanol (3 ml) was heated at reflux for 4 hours. The reaction wascooled, and the solvent was evaporated to dryness. The resulting residuewas purified by chromatography (silica gel, 1:1 acetone/hexane) to givethe desired product as a crystalline solid, which was recrystallizedfrom ethyl acetate and hexane to give pure4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine (145 mg, 42%): m. p.164-165° C. Anal. Calc'd for C₁₅H₁₃N₃ (235.29): C, 76.57; H, 5.57; N,17.86. Found: C, 76.49; H, 5.45; N, 17.70.

[0126] The compounds of Examples 2 through 8 were synthesized inaccordance with the chemistry described above (particularly in SchemeIII) by selection of the corresponding starting reagents:

[0127] The cyanoketone 1 of Scheme III wherein X is p-fluoro wassynthesized according to the procedure of I. Lantos et al., J. Org.Chem., 53, 4223-4227 (1988), which is incorporated herein by reference.A solution of the cyanoketone (10 g, 41 mmol), hydrazine hydrate (2.5ml) and acetic acid (5.2 ml) in benzene (100 ml) was refluxed for 4hours. The reaction was cooled and extracted with 3N HCl. The combinedacid extracts were basified to pH 10 using concentrated ammoniumhydroxide with cooling. The basic aqueous layer was extracted withmethylene chloride and the combined organic extracts were dried overmagnesium sulfate.

[0128] The drying agent was filtered and the filtrate concentrated invacuo to give the crude4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine which was purifiedby recrystallization from ethyl acetate and hexane. Purified4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine had m.p. 178-180°C. (capillary).

[0129] Anal. Calc'd for C₁₄H₁₁N₄F+0.25 H₂O: C, 64.99; H, 4.48; N, 21.65.Found: C, 64.99; H, 4.48; N, 21.54.

N-[4 (4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide

[0130] A solution of4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as setforth in Example 2 (200 mg, 0.77 mmol) and methanesulfonyl chloride (90mg) in pyridine (5 ml) was stirred at room temperature overnight. Thepyridine was removed in vacuo and the residue was treated with methylenechloride and water. The resultant precipitate was filtered to giveN-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide.AdditionalN-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamidewas contained in the methylene chloride layer. The methylene chloridewas stripped in vacuo and the residue purified by chromatography onsilica gel using mixtures of ethyl acetate and methanol as eluents. ThepurifiedN-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamidehad m.p. 168-170° C.

[0131] Anal. Calc'd for C₁₅H₁₃N₄SO₂F+0.25 H₂O: C, 53.48; H, 4.04; N,16.63. Found: C, 53.41; H, 3.78; N, 16.52.

N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylsulfamide

[0132] Methyl sulfamyl chloride was synthesized by refluxing a solutionof methylsulfamic acid (1.0 g) in phosphorus oxychloride (10 mL) for 6hours. The excess phosphorus oxychloride was removed in vacuo and theresidual oil was used for the synthesis of the product without furthertreatment. A solution of4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as setforth in Example 2 (200 mg, 0.77 mmol) and approximately 1 mmol of theabove oil in pyridine (5 ml) was stirred at room temperature for 2hours. The reaction was stripped in vacuo and the residue purified bychromatography on silica gel using ethyl acetate and mixtures of ethylacetate and methanol as eluents to giveN-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-1-yl]-N′-methylsulfamideas a crystalline solid, m. p. 194-195° C.

[0133] Anal. Calc'd for C₁₅H₁₄N₅SO₂F+1.0 H₂O: C, 49.31; H, 4.41; N,19.17. Found: C, 49.13; H, 3.97; N, 19.01.

[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]urea

[0134] A suspension of4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as setforth in Example 2 (200 mg, 0.77 mmol) in a solution of di-tert-butylcarbonate (185 mg, 0.9 mmol) and 4-dimethylaminopyridine (DMAP) (10 mg)in methylene chloride (10 ml) was stirred at room temperature for 20minutes, during which time, the suspended material dissolved.N-Propylamine (50 mg) was added and stirring was continued at roomtemperature for 1 hour. The reaction was then refluxed for 15 minutes,cooled and stripped in vacuo. Treatment with ethyl acetate and hexaneresulted in the deposition of crystals of the tert-butoxycarbonylderivative, m.p. 183-184° C.

[0135] Anal. Calc'd for C₁₉H₁₉N₄O₂F: C, 64.40; H, 5.40; N, 15.81. Found:C, 64.66; H, 5.63; N, 15.63.

[0136] A solution of the tert-butoxycarbonyl derivative above (100 mg,0.3 mmol) in tetrahydrofuran was treated with ammonia at 80° C. in apressure bottle for 12 hours. The reaction was stripped in vacuo and theresidue was purified by chromatography on silica gel eluting withmixtures of ethyl acetate and methanol. The purified[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]urea thus obtainedhad m.p. 224-225° C.

[0137] Anal. Calc'd for C₁₅H₁₂N₅O: C, 60.60; H, 4.07; N, 23.56. Found:C, 60.21; H, 4.11; N, 23.30.

[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]sulfamide

[0138] Sulfamyl chloride was synthesized from chlorosulfonyl isocyanateaccording to the procedure described by R. Graf in Chemische Berichte,p. 509 (1959), which is incorporated herein by reference. A solution of4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as setforth in Example 2 (200 mg, 0.77 mmol), sulfamyl chloride (100 mg, 0.8mmol) and triethylamine (200 mg, 2 mmol) in benzene (5 ml) andacetonitrile (5 ml) was stirred at room temperature for 2 hours. Thereaction was stripped in vacuo and residue was treated with water andbasified to pH 7 with ammonium hydroxide. The resultant precipitate waspurified by chromatography on silica gel using mixtures of ethyl acetateand methanol as eluents. The purified[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]sulfamide thusobtained had m.p. 201-202° C.

[0139] Anal. Calc'd for C₁₄H₁₂N₅SO₂F: C, 50.44; H, 3.63; N, 21.01.Found: C, 50.43; H, 3.45; N, 20.89.

4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazol-5-amine

[0140] A solution of cyanoketone 1 of Scheme III wherein X is p-chloro(1.5 g, 5.19 mmol), methylhydrazine (0.35 ml) and acetic acid (0.75 ml)in benzene (15 ml) was refluxed for 3.5 hours. The reaction was cooledand extracted with 3N HCl. The aqueous layer was concentrated on therotary evaporator and then basified with ammonium hydroxide. Theresultant precipitate was recrystallized from methanol to give pure4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazol-5-amine, m.p.257-258° C.

[0141] Anal. Calc'd for C₁₅H₁₃N₄Cl: C, 63.27; H, 4.60; N, 19.68. Found:C, 62.93; H, 4.45; N, 19.64.

N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylurea

[0142] A solution of4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as setforth in Example 2 (100 mg, 0.38 mmol), methyl isocyanate (22 mg, 0.39mmol) and 4-dimethylaminopyridine (2.5 mg) in methylene chloride (10 ml)was stirred at room temperature for 30 minutes. The reaction wasstripped in vacuo. The residue was triturated with hexane and the solidfiltered to give pureN-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylurea, m.p. 212-213° C.

[0143] Anal. Calc'd for C₁₆H₁₄N₅FO: C, 61.73; H, 4.53; N, 22.50. Found:C, 61.63; H, 4.55; N, 22.47.

[0144] The compounds of Examples 9 through 11 were synthesized inaccordance with the chemistry described above (particularly in SchemeIV) by selection of the corresponding starting reagents:

4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine

[0145] Step 1

[0146] Methyl isonicotinate (13.7 g, 0.1 mole) and ethyl4-fluorophenylacetate (18.2 g, 0.1 mole) were mixed together, thensodium methoxide(8.1 g, 0.15 mole) was added. The mixture was heated to60-70° C. for 24 hours while nitrogen was blown through the flask toeliminate methanol. Concentrated hydrochloric acid (50 mL) then wasadded and the reaction mixture was refluxed for 3 hours. After additionof water (30 mL), the reaction mixture was extracted with chloroform,and the water phase was neutralized to pH 6-7 with aqueous sodiumhydroxide (1M). The precipitate formed was collected by filtration,washed with water and dried under vacuum to give 10 g of2-(4-fluorophenyl)-1-(4′-pyridyl)-ethan-1-one (yield: 46%). ¹H NMR:consistent with the assigned structure and/or its tautomer.

[0147] Step 2

[0148] 2-(4-fluorophenyl)-1-(4′-pyridyl)-ethan-1-one prepared above (1g) was dissolved in 50 mL tetrahydrofuran and N,N-dimethylformamidedimethyl acetal (5 mL) was added. The mixture was stirred at roomtemperature for 2 days. After evaporating the solvent, the solidobtained was washed with hexane and 1 g of the vinyl amine was obtained.This vinyl amine (0.5 g) was dissolved in ethanol (15 mL) and hydrazinehydrate (5 mL) was added. The mixture was stirred at 0° C. for 2 hoursand then evaporated to dryness. After recrystallization frommethanol/water, 400 mg of 4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridinewas obtained in 91% yield. MS, 240(M+L); ¹H NMR: consistent with theassigned structure; Anal. Calc'd for C₁₄H₁₀FN₃.0.2H₂O: C, 69.24; H,4.32; N, 17.30. Found: C, 69.54; H, 4.06; N, 17.43.

4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine Whenmethylhydrazine was substituted for hydrazine hydrate in Step 2 ofExample 9, 4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine (theN-methyl derivative corresponding to the compound of Example 9) wasobtained. Purification by recrystallization from toluene and hexane givethe pure 4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine in 579yield. MS m/z: 254 (M+1). ¹H NMR: consistent with the assignedstructure. Anal. calc'd for C₁₅H₁₂FN₃: C, 71.13; H, 4.78; N, 16.69.Found: C, 70.99; H, 4.68; N, 16.65.

[0149]

4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol and4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazole-1-ethanol

[0150] The procedure set forth in Example 9 was followed except that2-hydroxyethyl hydrazine was substituted for hydrazine hydrate.4-(4-Fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol and4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazole-1-ethanol were obtainedas a mixture by recrystallization from toluene and hexane in 67% yield.¹H NMR: consistent with the assigned structure. Mass spectrum, m/z: 284(M+1) . Anal. calc'd for C₁₆H₁₄FN₃O: C, 67.83; H, 4.98; N, 14.83. Found:C, 67.86; H, 5.04; N. 14.35.

[0151] The compounds of Examples 12 and 13 were synthesized inaccordance with the chemistry described above (particularly in Scheme V)by selection of the corresponding starting reagents:

4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamineand4-(4Fluorophenyl)-N,N-dimethyl-5-(4-pyridinyl)-1H-pyrazole-1-ethanamine

[0152] 4-(4-Fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol (or4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazole-ethanol) prepared as setforth in Example 11 (1.36 g) was dissolved in 30 mL pyridine and cooledto 0° C., whereupon methanesulfonyl chloride (0.6 mL) was added. Afterstirring at 0° C. for 12 hours, about 20 g of ice was added, and themixture was extracted with toluene (300 ml). After evaporation, theresidue was used directly without further purification. 0.7 g of theabove obtained compound was dissolved in methanol (25 miL), anddimethylamine/THF solution (4M, 2 mL) was added. The reaction on mixturewas refluxed for 12 hours, then evaporated to dryness. The residue waspurified by chromatography (methanol/dichloromethane 1:10). A mixture(0.59 g) of4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamineand4-(4-fluorophenyl)-N,N-dimethyl-5-(4-pyridinyl)-1H-pyrazole-1-ethanaminewere obtained. ¹H NMR: consistent with the assigned structure. Massspectrum, m/z: 311 (M+1). Anal. calc'd C₁₈H₁₉N₄F.0.55H₂O: C, 67.50; H,6.33; N, 17.49. Found: C, 67.21; H, 6.46; N, 17.14.

4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholineand4-[2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine

[0153] The procedure set forth in Example 11 was followed, except thatmorpholine was substituted for dimethylamine, to produce a mixture of4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholineand4-[2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine.Mass spectrum, m/z: 353 (M+1). Anal. calc'd for C₂₀H₂₁N₄OF+0.5H₂O: C,66.47; H, 6.14; N, 15.50. Found: C, 66.57; H, 6.27; N. 15.14.

[0154] The compound of Example 14 was synthesized in accordance with thechemistry described above (particularly in Scheme VI) by selection ofthe corresponding starting reagents:

4-[4-(4--fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine

[0155] 2-(4-fluorophenyl)-1-(4′-pyridyl)-ethan-1-one prepared as setforth in step 1 of Example 9 (0.5 g, 0.00232 moles) was mixed with of98% methyl hydrazine (0.2 g, 0.00462 moles) in 10 mL of ethanolcontaining 0.1 mL of acetic acid in a 50 mL Erlenmeyer flask. Aftergentle boiling (30 minutes on a steam bath) a small sample was evacuatedat high vacuum and examined by NMR to confirm completion of hydrazoneformation. The reaction mixture was concentrated to a pasty mass and 3.6mL of DMF dimethylacetal (0.027 moles) was then added and heated to 80°C. for 30 minutes, at which point a clear yellow viscous solution wasobtained. The reaction was checked for completion (TLC or NMR) andconcentrated and taken up in 20 mL of chloroform. After washing withwater (10 mL), the organic layer was extracted with 15 mL of 10% HCl.The water layer was then treated with 0.5 g of activated charcoal at 70°C. for 10 minutes, filtered through celite, neutralized cautiously to pH7-8 with vigorous stirring and cooling. The fine off-white precipitatewas filtered and dried. NMR was found to be in agreement with theproposed structure. The precipitate,4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine, obtained inquantitative yield was filtered, washed with ether and dried. Yield:0.45 g (77%). Mass spectrum, m/z: 254. Anal. calc'd: C, 62.18; H, 4.52;N. 14.50. Found: C, 62.39; H, 4.07; N, 14.24.

4-[4-(4-chlorcophenyl)-1H-pyrazol-3-yl]pyridine

[0156] 4-[4-(4-chlorcphenyl)-1H-pyrazol-3-yl]pyridine was preparedaccording to the procedure set forth in Example 9 except that ethyl4-chlorophenylacetate was substituted for ethyl 4-fluorophenylacetate;m.p. 204-207° C.

[0157] Anal. Calc'd: C, 65.76; H, 3.94; N, 16.43. Found: C, 65.44; H,3.78; N, 16.04.

4-(4-phenyl-1H-pyrazol-5-yl)pyridine

[0158] 4-(4-phenyl-1H-pyrazol-5-yl)pyridine can be prepared inaccordance with the procedure set forth in Example 9 by substitutingethylphenylacetate for ethyl 4-fluorophenylacetate.

1-methyl-4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]]piperidineand1-methyl-4-[2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-1-yl]piperidine

[0159] This compound can be prepared using the procedure sea forth forthe synthesis of the compound of Example 11 by substituting4-hydrazino-N-methylpiperidine for hydroxyethyl hydrazine.4-Hydrazino-N-methylpiperidine is synthesized as disclosed in Ebnoetheret al, Helv. Chim. Acta (1959) 42, 533, 541, 560. The resulting mixtureis separated into the respective pure title compounds by chromatographyon silica gel, eluting with methanol/dichloromethane (1:10), or othersuitable solvent system.

BIOLOGICAL EVALUATION

[0160] p38 Kinase Assay

[0161] Cloning of Human p38a

[0162] The coding region of the human p38a cDNA was obtained byPCR-amplification from RNA isolated from the human monocyte cell lineTHP.1. First strand cDNA was synthesized from total RNA as follows: 2 μgof RNA was annealed to 100 ng of random hexamer primers in a 10 μlreaction by heating to 70° C. for 10 minutes followed by 2 minutes onice. cDNA was then synthesized by adding 1 μl of RNAsin (Promega,Madison Wis.), 2 μl of 50 mM dNTP's, 4 μl of 5× buffer, 2 μl of 100 mMDTT and 1 μl (200 U) of is Superscript II ™ AMV reverse transcriptase.Random primer, dNTP's and Superscript ™ reagents were all purchased fromLife-Technologies, Gaithersburg, Mass. The reaction was incubated at 42°C. for 1 hour. Amplification of p38 cDNA was performed by aliquoting 5μl of the reverse transcriptase reaction into a 100 μl PCR reactioncontaining the following: 80 μl dH₂O, 2 μl 50 mM dNTP's, 1 μl each offorward and reverse primers (50 pmol/μl), 10 μl of 10× buffer and 1 μlExpand ™ polymerase (Boehringer Mannheim). The PCR primers incorporatedBam HI sites onto the 5′ and 3′ end of the amplified fragment, and werepurchased from Genosys. The sequences of the forward and reverse primerswere 5′-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3′ and5′GATCGAGGATTCTCAGGACTCCATCTCTTC-3′ respectively. The PCR amplificationwas carried out in a DNA Thermal Cycler (Perkin Elmer) by repeating 30cycles of 94° C. for 1 minute, 60° C. for 1 minute and 68° C. for 2minutes. After amplification, excess primers and unincorporated dNTP'swere removed from the amplified fragment with a Wizard ™ PCR prep(Promega) and digested with Bam HI (New England Biolabs). The Bam HIdigested fragment was ligated into BamHI digested pGEX 2T plasmid DNA(PharmaciaBiotech) using T-4 DNA ligase (New England Biolabs) asdescribed by T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nded. (1989). The ligation reaction was transformed into chemicallycompetent E. coli DH10B cells purchased from Life-Technologies followingthe manufacturer's instructions. Plasmid DNA was isolated from theresulting bacterial colonies using a Promega Wizard™ miniprep kit.Plasmids containing the appropriate Bam HI fragment were sequenced in aDNA Thermal Cycler (Perkin Elmer) with Prism™ (Applied Biosystems Inc.).cDNA clones were identified that coded for both human p38a isoforms (Leeet al. Nature 372, 739). One of the clones which contained the cDNA forp38a-2 (CSBP-2) inserted in the cloning site of pGEX 2T, 3′ of the GSTcoding region was designated pMON 35802. The sequence obtained for thisclone is an exact match of the CDNA clone reported by Lee et al. Thisexpression plasmid allows for the production of a GST-p38a fusionprotein.

[0163] Expression of Human p38a

[0164] GST/p38a fusion protein was expressed from the plasmid pMON 35802in E. coli, stain DH10B (Life Technologies, Gibco-BRL). Overnightcultures were grown in Luria Broth (LB) containing 100 mg/ml ampicillin.The next day, 500 ml of fresh LB was inoculated with 10 ml of overnightculture, and grown in a 2 liter flask at 37° C. with constant shakinguntil the culture reached an absorbance of 0.8 at 600 nm. Expression ofthe fusion protein was induced by addition of isopropylb-D-thiogalactosidse (IPTG) to a final concentration of 0.05 mM. Thecultures were shaken for three hours at room temperature, and the cellswere harvested by centrifugation. The cell pellets were stored frozenuntil protein purification.

[0165] Purification of p38 Kinase-α

[0166] All chemicals were from Sigma Chemical Co. unless noted. Twentygrams of E. coli cell pellet collected from five 1 L shake flaskfermentations was resuspended in a volume of PBS (140 mM NaCl, 2.7 mMKCl, 10 mM Na₂HPO₄, 1.8 MM KH₂PO₄, pH 7.3) up to 200 ml. The cellsuspension was adjusted to 5 mM DTT with 2 M DTT and then split equallyinto five 50 ml Falcon conical tubes. The cells were sonnicated(Ultrasonics model W375) with a 1 cm probe for 3×1 minutes (pulsed) onice. Lysed cell material was removed by centrifugation (12,000×g, 15minutes) and the clarified supernatant applied to glutathione-senharoseresin (Pharmacia).

[0167] Glutathione-Secharose Affinity Chromatography

[0168] Twelve ml of a 50% glutathione sepharose-PBS suspension was addedto 200 ml clarified supernatant and incubated batchwise for 30 minutesat room temperature. The resin was collected by centrifugation (600×g, 5min) and washed with 2×150 ml PBS/11 Triton X-100, followed by 4×40 mlPBS. To cleave the p38 kinase from the GST-p38 fusion protein, theglutathione-sepharose resin was resuspended in 6 ml PBS containing 250units thrombin protease (Pharmacia, specific activity>7500 units/mg) andmixed gently for 4 hours at room temperature. The glutathione-sepharoseresin was removed by centrifugation (600×g, 5 min) and washed 2×6 mlwith PBS. The PBS wash fractions and digest supernatant containing p28kinase protein were pooled and adjusted to 0.3 mM PMSF.

[0169] Mono Q Anion Exchange Chromatography

[0170] The thrombin-cleaved p38 kinase was further purified byFPLC-anion exchange chromatography. Thrombin-cleaved sample was diluted2-fold with Buffer A (25 mM HEPES, pH 7.5, 25 mM beta-glycerophosphate,2 mM DTT, 5% glycerol) and injected onto a Mono Q HR 10/10 (Pharmacia)anion exchange column equilibrated with Buffer A. The column was elutedwith a 160 ml 0.1 M-0.6 M NaCl/Buffer A gradient (2 ml/minute flowrate).The p38 kinase peak eluting at 200 mM NaCl was collected andconcentrated to 3-4 ml with a Filtron 10 concentrator (Filtron Corp.).

[0171] Sephacryl S100 Gel Filtration Chromatography

[0172] The concentrated Mono Q- p38 kinase purified sample was purifiedby gel filtration chromatography (Pharmacia Hiprep 26/60 Sephacryl S100column equilibrated with Buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mMDTT, 5% glycerol)). Protein was eluted from the column with Buffer B ata 0.5 ml/minute flowrate and protein was detected by absorbance at 280nm. Fractions containing p38 kinase (detected by SDS-polyacrylamide gelelectrophoresis) were pooled and frozen at −80° C. Typical purifiedprotein yields from 5 L E. coli shake flasks fermentations were 35 mgp38 kinase.

[0173] In Vitro Assay

[0174] The ability of compounds to inhibit human p38 kinase alpha wasevaluated using two in vitro assay methods. In the first method,activated human p38 kinase alpha phosphorylates a biotinylatedsubstrate, PHAS-I (phosphorylated heat and acid stable protein-insulininducible), in the presence of gamma ³²P-ATP (³²P-ATP).

[0175] PHAS-I was biotinylated prior to the assay and provides a meansof capturing the substrate which is phosphorylated during the assay. p38Kinase was activated by MKK6. Compounds were tested in 10 fold serialdilutions over the range of 100 μM to 0.001 μM using 1% DMSO. Eachconcentration of inhibitor was tested in triplicate.

[0176] All reactions were carried out in 96 well polypropylene plates.Each reaction well contained 25 mM HEPES pH 7.5, 10 mM magnesium acetateand 50 μM unlabeled ATP. Activation of p38 was required to achievesufficient signal in the assay. Biotinylated PHAS-I was used at 1-2 μgper 50 μl reaction volume, with a final concentration of 1.5 μM.Activated human p38 kinase alpha was used at 1 μg per 50 μl reactionvolume representing a final concentration of 0.3 μM. Gamma ³²P-ATP wasused to follow the phosphorylation of PHAS-I. ³²P-ATP has a specificactivity of 3000 Ci/mmol and was used at 1.2 μCi per 50 μl reactionvolume. The reaction Proceeded either for one hour or overnight at 30°C.

[0177] Following incubation, 20 μl of reaction mixture was transferredto a high capacity streptavidin coated filter plate(SAM-streptavidin-matrix, Promega) prewetted with phosphate bufferedsaline. The transferred reaction mix was allowed to contact thestreptavidin membrane of the Promega plate for 1-2 minutes. Followingcapture of biotinylated PHAS-I with ³²P incorporated, each well waswashed to remove unincorporated ³²P-ATP three times with 2M NaCl, threewashes of 2M NaCl with 1% phosphoric, three washes of distilled waterand finally a single wash of 95% ethanol. Filter plates were air driedand 20 μl of scintillant was added. The plates were sealed and counted.

[0178] A second assay format was also employed that is based on p38kinase alpha induced phosphorylation of EGFRP (epidermal growth factorreceptor peptide, a 21 mer) in the presence of ³³P-ATP. Compounds weretested in 10 fold serial dilutions over the range of 100μM to 0.001 μMin 1% DMSO. Each concentration of inhibitor was tested in triplicate.Compounds were evaluated in 50 μl reaction volumes in the presence of 25mM Hepes pH 7.5, 10 mM magnesium acetate, 4% glycerol, 0.4% bovine serumalbumin, 0.4 mM DTT, 50 μM unlabeled ATP, 25 μg EGFRP (200 μM), and 0.05uCi gamma ³³P-ATP. Reactions were initiated by addition of 0.09 μg ofactivated, purified human GST-p38 kinase alpha. Activation was carriedout using GST-MKK6 (5:1,p38:MKK6) for one hour at 30° C. in the presenceof 50 μM ATP. Following incubation for 60 minutes at room temperature,the reaction was stopped by addition of 150 μl of AG 1×8 resin in 900 mMsodium formate buffer, pH 3.0 (1 volume resin to 2 volumes buffer). Themixture was mixed three times with pipetting and the resin was allowedto settle. A total of 50 μl of clarified solution head volume wastransferred from the reaction wells to Microlite-2 plates. 150 μl ofMicroscint 40 was then added to each well of the Microlite plate, andthe plate was sealed, mixed, and counted.

[0179] TNF Cell Assays

[0180] Method of Isolation of Human Peripheral Blood Mononuclear Cells

[0181] Human whole blood was collected in Vacutainer tubes containingEDTA as an anticoagulant. A blood sample (7 ml) was carefully layeredover 5 ml PMN Cell Isolation Medium (Robbins Scientific) in a 15 mlround bottom centrifuge tube. The sample was centrifuged at 450-500×gfor 30-35 minutes in a swing out rotor at room temperature. Aftercentrifugation, the top band of cells were removed and washed 3 timeswith PBS w/o calcium or magnesium. The cells were centrifuged at 400×gfor 10 minutes at room temperature. The cells were resuspended inMacrophage Serum Free Medium (Gibco BRL) at a concentration of 2 millioncells/ml.

[0182] LPS Stimulation of Human PBMs

[0183] PBM cells (0.1 ml, 2 million/ ml) were co-incubated with 0.1 mlcompound (10-0.41 μM, final concentration) for 1 hour in flat bottom 96well microtiter plates. Compounds were dissolved in DMSO initially anddiluted in TCM for a final concentration of 0.1% DMSO. LPS (Calbiochem,20 ng/ml, final concentration) was then added at a volume of 0.010 ml.Cultures were incubated overnight at 37° C. Supernatants were thenremoved and tested by ELISA for TNF-a and IL1-b. Viability was analyzedusing MTS. After 0.1 ml supernatant was collected, 0.020 ml MTS wasadded to remaining 0.1 ml cells. The cells were incubated at 37° C. for2-4 hours, then the O.D. was measured at 490-650 nM.

[0184] Maintenance and Differentiation of the U937 Human HistiocyticLymphoma Cell Line

[0185] U937 cells (ATCC) were propagated in RPMI 1640 containing 10%Fetal bovine serum, 100 IU/ml penicillin, 100 μg/ml streptomycin, and 2mM glutamine (Gibco). Fifty million cells in 100 ml media were inducedto terminal monocytic differentiation by 24 hour incubation with 20ng/ml phorbol 12-myristate 13-acetate (Sigma). The cells were washed bycentrifugation (200×g for 5 min) and resuspended in 100 ml fresh medium.After 24-48 hours, the cells were harvested, centrifuged, andresuspended in culture medium at 2 million cells/ml.

[0186] LPS Stimulation of TNF production by U937 Cells

[0187] U937 cells (0.1 ml, 2 million/ml) were incubated with 0.1 mlcompound (0.004-50 μM, final concentration) for 1 hour in 96 wellmicrotiter plates. Compounds were prepared as 10 mM stock solutions inDMSO and diluted in culture medium to yield a final DMSO concentrationof 0.1% in the cell assay. LPS (E. coli, 100 ng/ml final concentration)was then added at a volume of 0.02 ml. After 4 hour incubation at 37°C., the amount of TNF-α released in the culture medium was quantitatedby ELISA. Inhibitory potency is expressed as IC50 (μM).

[0188] Rat Assay

[0189] The efficacy of the novel compounds in blocking the production ofTNF also was evaluated using a model based on rats challenged with LPS.Male Harlen Lewis rats [Sprague Dawley Co.] were used in this model.Each rat weighed approximately 300 g and was fasted overnight prior totesting. Compound administration was typically by oral gavage (althoughintraperitoneal, subcutaneous and intravenous administration were alsoused in a few instances) 1 to 24 hours prior to the LPS challenge. Ratswere administered 30 μg/kg LPS [salmonella typhosa, Sigma Co.]intravenously via the tail vein. Blood was collected via heart puncture1 hour after the LPS challenge. Serum samples were stored at −20° C.until quantitative analysis of TNF-α by Enzyme Linked-Immuno-SorbentAssay (“ELISA”) [Biosource]. Additional details of the assay are setforth in Perretti, M., et al., Br. J. Pharmacol. (1993), 110, 868-874,which is incorporated by reference in this application.

[0190] Mouse Assay

[0191] Mouse Model Of LPS-Induced TNF Aloha Production

[0192] TNF alpha was induced in 10-12 week old BALB/c female mice bytail vein injection with 100 ng lipopolysaccharide (from S. Typhosa) in0.2 ml saline. One hour later mice were bled from the retroorbital sinusand TNF concentrations in serum from clotted blood were quantified byELISA. Typically, peak levels of serum TNF ranged from 2-6 ng/ml onehour after LPS injection.

[0193] The compounds tested were administered to fasted mice by oralgavage as a suspension in 0.2 ml of 0.5% methylcellulose and 0.025%Tween 20 in water at 1 hour or 6 hours prior to LPS injection. The 1hour protocol allowed evaluation of compound potency at Cmax plasmalevels whereas the 6 hour protocol allowed estimation of compoundduration of action. Efficacy was determined at each time point aspercent inhibition of serum TNF levels relative to LPS injected micethat received vehicle only.

[0194] Induction And Assessment Of Collagen-Induced Arthritis In Mice

[0195] Arthritis was induced in mice according to the procedure setforth in J. M. Stuart, Collagen Autoimmune Arthritis, Annual Rev.Immunol. 2:199 (1984), which is incorporated herein by reference.Specifically, arthritis was induced in 8-12 week old DBA/1 male mice byinjection of 50 μg of chick type II collagen (CII) (provided by Dr.Marie Griffiths, Univ. of Utah, Salt Lake City, Utah) in completeFreund's adjuvant (Sigma) on day 0 at the base of the tail. Injectionvolume was 100 μl. Animals were boosted on day 21 with 50 μg of CII inincomplete Freund's adjuvant (100 μl volume). Animals were evaluatedseveral times each week for signs of arthritis. Any animal with pawredness or swelling was counted as arthritic. Scoring of arthritic pawswas conducted in accordance with the procedure set forth in Wooley etal., Genetic Control of Type II Collagen Induced Arthritis in Mice:Factors Influencing Disease Suspectibility and Evidence for Multiple MHCAssociated Gene Control., Trans. Proc., 15:180 (1983). Scoring ofseverity was carried out using a score of 1-3 for each paw (maximalscore of 12/mouse). Animals displaying any redness or swelling of digitsor the paw were scored as 1. Gross swelling of the whole paw ordeformity was scored as 2. Ankylosis of joints was scored as 3. Animalswere evaluated for 8 weeks. 8-10 animals per group were used.

[0196] Preparation And Administration Of Compounds

[0197] The compounds tested on mice having collagen-induced arthritiswere prepared as a suspension in 0.5% methylcelluose (Sigma, St. Louis,Mo.), 0.025% Tween 20 (Sigma). The compound suspensions wereadministered by oral gavage in a volume of 0.1 ml b.i.d. Administrationbegan on day 20 post collagen injection and continued daily until finalevaluation on day 56. Scoring of arthritic paws was conducted as setforth above.

[0198] Results obtained using the above-described assays are se, forthin Table I below. p38 assay and U937 cell assay results are expressed asIC₅₀ (μm). Mouse-LPS assay results are expressed as percent inhibition.TABLE I mLPS P38α¹ p38α² U937 (6 h @ Example (μM) (μM) (μM) (30 mpk) 130.00 13.35 10.00 2 6.21 10.61 3 2.55 >10.00 4 0.23 4.70 54 5 1.98 5.536 10.00 7 5.48 10.00 8 10.00 9 2.44 3.46 0.6474 42 10 7.23 0.4 1.5987 7611 0.695 10 40 12 0.941 10 −5 13 0.86 >10 22 15 5.9 0.75 32

[0199] Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of this invention inassociation with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The active compounds andcomposition may, for example, be administered orally, intravascularly(IV), intraperitoneally, subcutaneously, intramuscularly (IM) ortopically.

[0200] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, hard or soft capsule, lozenges,dispensable powders, suspension or liquid. The pharmaceuticalcomposition is preferably made in the form of a dosage unit containing aparticular amount of the active ingredient. Examples of such dosageunits are tablets or capsules. The active ingredient may also beadministered by injection (IV, IM, subcutaneous or jet) as a compositionwherein, for example, saline, dextrose, or water may be used as asuitable carrier. The pH of the composition may be adjusted, ifnecessary, with suitable acid, base, or buffer. Suitable bulking,dispersing, wetting or suspending agents, including mannitol and PEG400, may also be included in the composition. A suitable parenteralcomposition can also include a compound formulated as a sterile solidsubstance, including lyophilized powder, in injection vials. Aqueoussolution can be added to dissolve the compound prior to injection. Theamount of therapeutically active compounds that are administered and thedosage regimen for treating a disease condition with the compoundsand/or compositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, theseverity of the inflammation or inflammation related disorder, the routeand frequency of administration, and the particular compound employed,and thus may vary widely. The pharmaceutical compositions may containactive ingredients in the range of about 0.1 to 1000 mg, preferably inthe range of about 7.0 to 350 mg. A daily dose of about 0.01 to 100mg/kg body weight, preferably between about 0.1 and about 50 mg/kg bodyweight and most preferably between about 0.5 to 30 mg/kg body weight,may be appropriate. The daily dose can be administered in one to fourdoses per day. In the case of skin conditions, it may be preferable toapply a topical preparation of compounds of this invention to theaffected area two to four times a day. For disorders of the eye or otherexternal tissues, e.g., mouth and skin, the formulations are preferablyapplied as a topical gel, spray, ointment or cream, or as a suppository,containing the active ingredients in a total amount of, for example,0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to15% w/w. When formulated in an ointment, the active ingredients may beemployed with either paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane. The transdermal patch may include the compound in a suitablesolvent system with an adhesive system, such as an acrylic emulsion, anda polyester patch. The oily phase of the emulsions of this invention maybe constituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others. The choice of suitable oils or fats for the formulation isbased on achieving the desired cosmetic properties, since the solubilityof the active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

[0201] Formulations suitable for topical administration to the eye alsoinclude eye drops wherein the active ingredients are dissolved orsuspended in suitable carrier, especially an aqueous solvent for theactive ingredients. The antiinflammatory active ingredients arepreferably present in such formulations in a concentration of 0.5 to20%, advantageously 0.5 to 10% and particularly about 1.5% w/w. Fortherapeutic purposes, the active compounds of this combination inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

[0202] All patent documents listed herein are incorporated by reference.Although this invention has been described with respect to specificembodiments, the derails of these embodiments are not to be construed aslimitations.

What is claimed is:
 1. A compound of Formula I

wherein R¹ is selected from hydrido, alkyl, cycloalkyl, alkenyl,alkynyl, heterocyclyl, cycloalkylalkylene, haloalkyl, hydroxyalkyl,aralkyl, alkoxyalkyl, mercaptoalkyl, alkylthioalkylene, amino,alkylamino, arylamino, aminoalkyl, alkylaminoalkylene,heterocyclylalkylene, aminocarbonylalkylene, andalkylaminocarbonylalkylene; and R² is selected from hydrido, alkyl,alkenyl, alkynyl, heterocyclyl, haloalkyl, heterocyclylalkyl, amino,alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl,carboxyalkyl, aminocarbonylamino, alkylaminocarbonylamino,alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, aminosulfonylamino,alkylaminosulfonylamino, and alkynylamino; wherein the heterocyclyl andheterocyclylalkyl groups are optionally substituted with one or moreradicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,haloalkyl, amino, cyano, and hydroxy; and Ar¹ is aryl optionallysubstituted with one or more radicals independently selected from halo,alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy, alkylthio,alkylsulfinyl, alkylsulfonyl, amino, aminocarbonyl, cyano,alkoxycarbonyl, formyl, aminosulfonyl, alkylamino, nitro, arylamino,alkylcarbonylamino, halosulfonyl, aminoalkyl, and haloalkyl; and HetAr²is pyridinyl, pyrimidinyl or quinolinyl optionally substituted with oneor more radicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, heterocyclyl, alkoxy, aralkoxy, haloalkyl,amino, cyano, aralkyl, alkylamino, cycloalkylamino, cycloalkenylamino,arylamino, alkynylamino, and aralkylamino; or apharmaceutically-acceptable salt or a tautomer thereof.
 2. A compound ofclaim 1 wherein R¹ is selected from hydrido, lower alkyl, lowercycloalkyl, lower cycloalkylalkylene, lower haloalkyl, lowerhydroxyalkyl, lower alkenyl, lower alkynyl, lower heterocyclyl, loweraralkyl, lower alkoxyalkyl, lower mercaptoalkyl, loweralkylthioalkylene, amino, lower alkylamino, lower arylamino, loweraminoalkyl, lower alkylaminoalkylene, lower heterocyclylalkylene, loweraminocarbonylalkylene, and lower alkylaminocarbonylalkylene; and R² isselected from hydrido, lower alkyl, lower alkenyl, lower alkynyl, lowerhaloalkyl, lower heterocyclyl, lower heterocyclylalkylene, amino, loweralkylamino, lower alkynylamino, lower aminoalkyl, lower alkylthio, lowercarboxy, lower alkoxycarbonyl, lower carboxyalkyl, loweraminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonyl,lower aminosulfonyl, lower alkylsulfonylamino, lower aminosulfonylamino,and lower alkylaminosulfonylamino, wherein the heterocyclyl andheterocyclylalkyl groups are optionally substituted with one or moreradicals independently selected from lower alkylthio, loweralkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, lower alkoxy,aryloxy, lower heterocyclyl, lower haloalkyl, amino, and cyano; and Ar¹is selected from phenyl, biphenyl, and naphthyl, wherein Ar¹ isoptionally substituted with one or more radicals independently selectedfrom lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halo, loweralkyl, lower alkenyl, lower alkynyl, lower alkylsulfinyl, cyano, loweralkoxycarbonyl, aminocarbonyl, formyl, lower alkylcarbonylamino, lowerhaloalkyl, lower alkoxy, lower alkenyloxy, lower alkyldioxy, amino,lower alkylamino, lower aminoalkyl, arylamino, nitro, and halosulfonyl;and HetAr² is pyridinyl or pyrimidinyl optionally substituted with oneor more radicals independently selected From lower alkylthio, loweralkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, lowerheterocyclyl, lower alkoxy, lower aralkoxy, lower haloalkyl, amino,cyano, lower aralkyl, lower alkylamino, lower cycloalkylamino, lowerarylamino, lower alkynylamino, and lower aralkylamino; or apharmaceutically-acceptable salt or tautomer thereof.
 3. A Compound ofclaim 2 wherein R¹ is selected from hydrido, methyl, ethyl, isopropyl,tert-butyl, isobutyl, trichloroethyl, pentafluoroethyl,heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, vinyl, allyl, ethynyl, propargyl, morpholinyl,piperidinyl, piperazinyl, benzyl, phenylethyl, morpholinomethyl,morpholinoethyl, pyrrolidinylmethyl, piperazinylmethyl,piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl,ethoxymethyl, amino, methylamino, dimethylamino, phenylamino,methylaminomethyl, dimethylaminomethyl, methylaminoethyl,dimethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl,cyclohexylmethyl, hydroxymethyl, hydroxyethyl, methylthio, andmethylthiomethyl; and R² is selected from hydrido, methyl, ethyl,propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, amino, N-methylamino, N,N-dimethylamino, ethynylamino,propargylamino, piperidinyl, piperazinyl, morpholinomethyl,pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl,pyridinylmethyl, thienylmethyl, thiazolylmethyl, oxazolylmethyl,pyrimidinylmerhyl, quinolylmethyl, isoquinolinylmethyl,imidazolylmethyl, benzimidazolylmethyl, furylmethyl, pyrazinylmethyl,aminocarbonylamino, methylaminocarbonylamino,dimethylaminocarbonylamino, ethylaminocarbonylamino,diethylaminocarbonylamino, methylsulfonylamino, ethylsulfonylamino,aminosulfonylamino, methylaminosulfonylamino, dimethylaminosulfonylamino, ethylaminosulfonylamino, and diethylaminosulfonylamino; and Ar¹ isselected from phenyl, biphenyl, and naphthyl, wherein Ar¹ is optionallysubstituted with one or more radicals independently selected frommethylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo,aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano,methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,dichloromethyl, chloromethyl, allyl, vinyl, ethynyl, propargyl, methoxy,ethoxy, propyloxy, n-butoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, aminomethyl, aminoethyl, N-methyl,N-phenylamino, phenylamino, diphenylamino, nitro, and chlorosulfonyl;and HetAr² is selected from pyridinyl and pyrimidinyl, wherein HetAr² isoptionally substituted with one or more radicals independently selectedfrom methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo,methyl, ethyl, isopropyl, tert-butyl, isobutyl, methoxyl, ethoxyl,phenoxyl, benzoxyl, phenethyl, trifluoromethyl, fluoromethyl,difluoromethyl, amino, benzylamino, propargylamino, cyclopropylamino,cyclobutylamino, cyclopentylamino, and cyano; or apharmaceutically-acceptable salt or tautomer thereof.
 4. A compound ofclaim 3 wherein R¹ is hydrido, methyl, ethyl, hydroxyethyl, propargyl,dimethylaminoethyl or morpholinoethyl; and R² is selected from hydrido,methyl, ethyl, amino, aminocarbonylamino, methylaminocarbonylamino,methylsulfonylamino, aminosulfonylamino, and methylaminosulfonylamino;and Ar¹ is phenyl optionally substituted with one or more radicalsindependently selected from methylthio, methylsulfinyl, methylsulfonyl,fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl,tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl,aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl,fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, methoxy,ethoxy, propyloxy, n-butoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, aminomethyl, aminoethyl, N-methyl,N-phenylamino, phenylamino, diphenylamino, nitro, and chlorosulfonyl;and HetAr² is optionally substituted with one or more radicalsindependently selected from methylthio, methylsulfinyl, methylsulfonyl,fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl,methoxyl, ethoxyl, phenoxyl, benzoxyl, trifluoromethyl, fluoromethyl,difluoromethyl, amino, propargylamino, and cyano; or apharmaceutically-acceptable salt or a tautomer thereof.
 5. A compound ofclaim 4 wherein R¹ is hydrido or methyl; and R² is hydrido or methyl;and Ar¹ is phenyl which is optionally substituted with one or moreradicals independently selected fluoro, chloro, methyl, ethyl,trifluoromethyl, methoxy, ethoxy, dimethylamino, and nitro; and HetAr²is optionally substituted with one or more radicals independentlyselected from methyl, chloro, fluoro, and trifluoromethyl; or apharmaceutically-acceptable salt or tautomer thereof.
 6. A compound ofclaim 1 wherein R² is hydrido.
 7. A compound of claim 2 wherein R² ishydrido.
 8. A compound of claim 3 wherein R² is hydrido.
 9. A compoundof claim 4 wherein R² is hydrido.
 10. A compound of claim 5 wherein R²is hydrido.
 11. A compound of claim 1 wherein HetAr² is optionallysubstituted pyridinyl.
 12. A compound of claim 2 wherein HetAr² isoptionally substituted pyridinyl.
 13. A compound of claim 3 whereinHetAr² is optionally substituted pyridinyl.
 14. A compound of claim 4wherein HetAr² is optionally substituted pyridinyl.
 15. A compound ofclaim 5 wherein HetAr² is optionally substituted pyridinyl.
 16. Acompound of claim 1 wherein R² is hydrido, Ar¹ is optionally substitutedphenyl, and HetAr² is optionally substituted pyridinyl.
 17. A compoundof claim 2 wherein R² is hydrido, Ar¹ is optionally substituted phenyl,and HetAr² is optionally substituted pyridinyl.
 18. A compound of claim3 wherein R² is hydrido, Ar¹ is optionally substituted phenyl, andHetAr² is optionally substituted pyridinyl.
 19. A compound of claim 4wherein R² is hydrido and HetAr² is optionally substituted pyridinyl.20. A compound of claim 5 wherein R² is hydrido and HetAr² is optionallysubstituted pyridinyl.
 21. A compound of claim 4 selected from thecompounds, their tautomers and their pharmaceutically acceptable salts,of the group consisting of4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine;4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine;N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide;N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylsulfamide;[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]urea;[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]sulfamide;4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazol-5-amine;N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylurea;4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine;4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine;4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol;4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine;4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine;4-[4-(4-chlorophenyl)-1H-pyrazol-3-yl]pyridine;1-methyl-4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]]piperidine;and1-methyl-4-[2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-1-yl]piperidine.22. A compound of Formula I

wherein R¹ is selected from hydrido, lower alkyl, lower cycloalkyl,lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, loweralkynyl, lower aralkyl, lower alkoxyalkyl, lower mercaptoalkyl, loweralkylthioalkylene, amino, lower alkylamino, lower arylamino, loweraminoalkyl, lower alkylaminoalkylene, lower heterocyclylalkylene, loweraminocarbonylalkylene, and lower alkylaminocarbonylalkylene; and R² isselected from hydrido, lower alkyl, lower cycloalkyl, lowercycloalkenyl, aryl selected from phenyl and biphenyl, lower aralkyl,lower haloalkyl, lower heterocyclyl, lower heterocyclylalkylene, amino,lower arylamino, lower alkylamino, lower alkynylamino, loweraminocarbonylamino, lower alkylaminocarbonylamino, sulfonyl, loweralkylsulfonylamino, lower aminosulfonylamino, and loweralkylaminosulfonylamino, wherein the cycloalkyl, aryl and heterocyclylgroups are optionally substituted with one or more radicalsindependently selected from lower alkylthio, lower alkylsulfonyl, loweralkylsulfinyl, halo, lower alkyl, lower alkoxy, aryloxy, lowerheterocyclyl, lower haloalkyl, amino, and cyano; and Ar¹ is phenyloptionally substituted with one or more radicals independently selectedfrom halo, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy,lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, amino,aminocarbonyl, cyano, lower alkoxycarbonyl, formyl, aminosulfonyl, loweralkylamino, nitro, lower arylamino, lower alkylcarbonylamino,halosulfonyl, lower aminoalkyl, and lower haloalkyl; and HetAr² ispyridinyl optionally substituted with one or more radicals independentlyselected from lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl,halo, lower alkyl, lower heterocyclyl, lower alkoxy, lower aralkoxy,lower haloalkyl, amino, cyano, lower aralkyl, lower alkylamino, lowercycloalkylamino, lower aralkylamino, and lower arylamino; or apharmaceutically-acceptable salt or a tautomer thereof.
 23. A compoundof claim 22 wherein R¹ is hydrido, methyl, hydroxyethyl,dimethylaminoethyl, propargyl, or morpholinoethyl; and R² is selectedfrom hydrido, methyl, ethyl, amino, aminocarbonylamino,methylaminocarbonylamino, methylsulfonylamino, aminosulfonylamino, andmethylaminosulfonylamino;
 24. A compound of claim 22 wherein R² ishydrido.
 25. A compound of claim 22 wherein Ar¹ is phenyl substitutedwith one or more halogen radicals.
 26. A compound of claim 22 wherein R²is hydrido and Ar¹ is phenyl substituted with one or more halogenradicals.
 27. A pharmaceutical composition comprising atherapeutically-effective amount of a compound, said compound selectedfrom the compounds of claim 1; or a pharmaceutically salt or tautomerthereof.
 28. A pharmaceutical composition comprising atherapeutically-effective amount of a compound, said compound selectedfrom the compounds of claim 2; or a pharmaceutically salt or tautomerthereof.
 29. A pharmaceutical composition comprising atherapeutically-effective amount of a compound, said compound selectedfrom the compounds of claim 3; or a pharmaceutically salt or tautomerthereof.
 30. A pharmaceutical composition comprising atherapeutically-effective amount of a compound, said compound selectedfrom the compounds of claim 4; or a pharmaceutically salt or tautomerthereof.
 31. A pharmaceutical composition comprising atherapeutically-effective amount of a compound, said compound selectedfrom the compounds of claim 5; or a pharmaceutically salt or tautomerthereof.
 32. A pharmaceutical composition comprising atherapeutically-effective amount of a compound, said compound selectedfrom the compounds of claim 21; or a pharmaceutically salt or tautomerthereof.
 33. A method of treating a TNF mediated disorder, said methodcomprising treating the subject having or susceptible to such disorderwith a therapeutically-effective amount of a compound of Formula I

wherein R¹ is selected from hydrido, alkyl, cycloalkyl, alkenyl,alkynyl, heterocyclyl, cycloalkylalkylene, haloalkyl, hydroxyalkyl,aralkyl, alkoxyalkyl, mercaptoalkyl, alkylthioalkylene, amino,alkylamino, arylamino, aminoalkyl, alkylaminoalkylene,heterocyclylalkylene, aminocarbonylalkylene, andalkylaminocarbonylalkylene; and R² is selected from hydrido, alkyl,alkenyl, alkynyl, heterocyclyl, haloalkyl, heterocyclylalkyl, amino,alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl,carboxyalkyl, aminocarbonylamino, alkylaminocarbonylamino,alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, aminosulfonylamino,alkylaminosulfonylamino,and alkynylamino; wherein the heterocyclyl andheterocyclylalkyl groups are optionally substituted with one or moreradicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,haloalkyl, amino, cyano, and hydroxy; and Ar¹ is aryl optionallysubstituted with one or more radicals independently selected from halo,alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy, alkylthio,alkylsulfinyl, alkylsulfonyl, amino, aminocarbonyl, cyano,alkoxycarbonyl, formyl, aminosulfonyl, alkylamino, nitro, arylamino,alkylcarbonylamino, halosulfonyl, aminoalkyl, and haloalkyl; and HetAr²is pyridinyl, pyrimidinyl or quinolinyl optionally substituted with oneor more radicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, heterocyclyl, alkoxy, aralkoxy, haloalkyl,amino, cyano, aralkyl, alkylamino, cycloalkylamino, cycloalkenylamino,arylamino, alkynylamino, and aralkylamino; or apharmaceutically-acceptable salt or a tautomer thereof.
 34. A method oftreating a p38 kinase mediated disorder, said method comprising treatingthe subject having or susceptible to such disorder with atherapeutically-effective amount of a compound of Formula I

wherein R¹ is selected from hydrido, alkyl, cycloalkyl, alkenyl,alkynyl, heterocyclyl, cycloalkylalkylene, haloalkyl, hydroxyalkyl,aralkyl, alkoxyalkyl, mercaptoalkyl, alkylthioalkylene, amino,alkylamino, arylamino, aminoalkyl, alkylaminoalkylene,heterocyclylalkylene, aminocarbonylalkylene, andalkylaminocarbonylalkylene; and R² is selected from hydrido, alkyl,alkenyl, alkynyl, heterocyclyl, haloalkyl, heterocyclylalkyl, amino,alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl,carboxyalkyl, aminocarbonylamino, alkylaminocarbonylamino,alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, aminosulfonylamino,alkylaminosulfonylamino, and alkynylamino; wherein the heterocyclyl andheterocyclylalkyl groups are optionally substituted with one or moreradicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,haloalkyl, amino, cyano, and hydroxy; and Ar¹ is aryl optionallysubstituted with one or more radicals independently selected from halo,alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy, alkylthio,alkylsulfinyl, alkylsulfonyl, amino, aminocarbonyl, cyano,alkoxycarbonyl, formyl, aminosulfonyl, alkylamino, nitro, arylamino,alkylcarbonylamino, halosulfonyl, aminoalkyl, and haloalkyl; and HetAr²is pyridinyl, pyrimidinyl or quinolinyl optionally substituted with oneor more radicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, heterocyclyl, alkoxy, aralkoxy, haloalkyl,amino, cyano, aralkyl, alkylamino, cycloalkylamino, cycloalkenylamino,arylamino, alkynylamino, and aralkylamino; or apharmaceutically-acceptable salt or a tautomer thereof.
 35. A method oftreating inflammation, said method comprising treating the subjecthaving or susceptible to such condition with a therapeutically-effectiveamount of a compound of formula I

wherein R¹ is selected from hydrido, alkyl, cycloalkyl, alkenyl,alkynyl, heterocyclyl, cycloalkylalkylene, haloalkyl, hydroxyalkyl,aralkyl, alkoxyalkyl, mercaptoalkyl, alkylthioalkylene, amino,alkylamino, arylamino, aminoalkyl, alkylaminoalkylene,heterocyclylalkylene, aminocarbonylalkylene, andalkylaminocarbonylalkylene; and R² is selected from hydrido, alkyl,alkenyl, alkynyl, heterocyclyl, haloalkyl, heterocyclylalkyl, amino,alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl,carboxyalkyl, aminocarbonylamino, alkylaminocarbonylamino,alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, aminosulfonylamino,alkylaminosulfonylamino, and alkynylamino; wherein the heterocyclyl andheterocyclylalkyl groups are optionally substituted with one or moreradicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,haloalkyl, amino, cyano, and hydroxy; and Ar¹ is aryl optionallysubstituted with one or more radicals independently selected from halo,alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy, alkylthio,alkylsulfinyl, alkylsulfonyl, amino, aminocarbonyl, cyano,alkoxycarbonyl, formyl, aminosulfonyl, alkylamino, nitro, arylamino,alkylcarbonylamino, halosulfonyl, aminoalkyl, and haloalkyl; and HetAr²is pyridinyl, pyrimidinyl or quinolinyl optionally substituted with oneor more radicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, heterocyclyl, alkoxy, aralkoxy, haloalkyl,amino, cyano, aralkyl, alkylamino, cycloalkylamino, cycloalkenylamino,arylamino, alkynylamino, and aralkylamino; or apharmaceutically-acceptable salt or a tautomer thereof.
 36. A method oftreating arthritis, said method comprising treating the subject havingor susceptible to such condition with a therapeutically-effective amountof a compound of Formula I

wherein R¹ is selected from hydrido, alkyl, cycloalkyl, alkenyl,alkynyl, heterocyclyl, cycloalkylalkylene, haloalkyl, hydroxyalkyl,aralkyl, alkoxyalkyl, mercaptoalkyl, alkylthioalkylene, amino,alkylamino, arylamino, aminoalkyl, alkylaminoalkylene,heterocyclylalkylene, aminocarbonylalkylene, andalkylaminocarbonylalkylene; and R² is selected from hydrido, alkyl,alkenyl, alkynyl, heterocyclyl, haloalkyl, heterocyclylalkyl, amino,alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl,carboxyalkyl, aminocarbonylamino, alkylaminocarbonylamino,alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, aminosulfonylamino,alkylaminosulfonylamino, and alkynylamino; wherein the heterocyclyl andheterocyclylalkyl groups are optionally substituted with one or moreradicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,haloalkyl, amino, cyano, and hydroxy; and Ar¹ is aryl optionallysubstituted with one or more radicals independently selected from halo,alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy, alkylthio,alkylsulfinyl, alkylsulfonyl, amino, aminocarbonyl, cyano,alkoxycarbonyl, formyl, aminosulfonyl, alkylamino, nitro, arylamino,alkylcarbonylamino, halosulfonyl, aminoalkyl, and haloalkyl; and HetAr²is pyridinyl, pyrimidinyl or quinolinyl optionally substituted with oneor more radicals independently selected from alkylthio, alkylsulfonyl,alkylsulfinyl, halo, alkyl, heterocyclyl, alkoxy, aralkoxy, haloalkyl,amino, cyano, aralkyl, alkylamino, cycloalkylamino, cycloalkenylamino,arylamino, alkynylamino, and aralkylamino; or apharmaceutically-acceptable salt or a tautomer thereof.
 37. The methodof claim 33 wherein the TNF mediated disorder is selected from the groupof disorders consisting of bone resorption, graft vs. host reaction,atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout,psoriasis, topical inflammatory disease state, adult respiratorydistress syndrome, asthma, Chronic pulmonary inflammatory disease,cardiac reperfusion injury, renal reperfusion injury, thrombus,glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatorybowel disease and cachexia.
 38. The method of claim 33 wherein the TNFmediated disorder is inflammation.
 39. The method of claim 33 whereinthe TNF mediated disorder is arthritis.
 40. The method of claim 33wherein the TNF mediated disorder is asthma.
 41. The method of claim 33wherein the compound is selected from the compounds, their tautomers andtheir pharmaceutically acceptable salts, of the group consisting of4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine;4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine;N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide;N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylsulfamide;[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]urea;[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]sulfamide;4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazol-5-amine;N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylurea;4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine;4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine;4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol;4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine;4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine;4-[4-(4-chlorcphenyl)-1H-pyrazol-3-yl]pyridine;1-methyl-4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]]piperidine;and1-methyl-4-[2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-1-yl]piperidine.42. The method of claim 34 wherein the disorder is a p38α kinasemediated disorder.
 43. The method of claim 34 wherein the P38 kinasemediated disorder is selected from the group of disorders consisting ofbone resorption, graft vs. host reaction, atherosclerosis, arthritis,osteoarthritis, rheumatoid arthritis, gout, psoriasis, topicalinflammatory disease state, adult respiratory distress syndrome, asthma,chronic pulmonary inflammatory disease, cardiac reperfusion injury,renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease,ulcerative colitis, inflammatory bowel disease and cachexia.
 44. Themethod of claim 34 wherein the p38 kinase mediated disorder isinflammation.
 45. The method of claim 34 wherein the p38 kinase mediateddisorder is arthritis.
 46. The method of claim 34 wherein the p38 kinasemediated disorder is asthma.
 47. The method of claim 34 wherein thecompound is selected from the compounds, their tautomers and theirpharmaceutically acceptable salts, of the group consisting of4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine;4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine;N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide;N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylsulfamide;[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]urea;[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]sulfamide;4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazol-5-amine;N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylurea;4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine;4-[4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]pyridine;4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol;4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine;4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine;4-[4-(4-chlorophenyl)-1H-pyrazol-3-yl]pyridine;1-methyl-4-[2-[4-(4-fluorophenyl)-3-(4-pyridinyl)-1H-pyrazol-1-yl]]piperidine;and1-methyl-4-[2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-1-yl]piperidine.48. A compound of claim 1 that is4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine or apharmaceutically-acceptable salt or a tautomer thereof.
 49. The methodof claim 33 wherein the compound is4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine or apharmaceutically-acceptable salt or a tautomer thereof.
 50. The methodof claim 34 wherein the compound is4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine or apharmaceutically-acceptable salt or a tautomer thereof.